Implantable and biodegradable drug delivery devices and methods of use thereof

ABSTRACT

Provided are implantable and biodegradable drug delivery devices capable of delivering an active pharmaceutical ingredient (API) directly to a target tissue site. The drug delivery devices can include at least two layers. One of the layers can include the API and a biodegradable polymer and a second layer can include another biodegradable polymer that degrades slower than the first biodegradable polymer. When the device is placed directly on the target tissue, the API layer can degrade thereby releasing the API towards the target tissue while the non-API layer can prevent the API from being released away from the target tissue onto non-target tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/280,497, filed Nov. 17, 2021, and U.S. Provisional Application No.63/391,535, filed Jul. 22, 2022, the entire contents of each of whichare incorporated herein by reference.

FIELD OF THE DISCLOSURE

This relates to implantable drug delivery devices. Specifically, thisrelates to implantable and biodegradable drug delivery devices thatdeliver active pharmaceutical ingredients to local tissue sites.

BACKGROUND OF THE DISCLOSURE

Most of the work being done in the cancer space is based on new ways touse or package existing systemic chemotherapies. In other words, mostresearchers are either testing chemotherapies that have been approved inother cancers, or testing new IV delivery methods such as liposomes.However, the major limit of existing chemotherapy effectiveness is dueto systemic off-target toxicity. For example, only 1-5% of achemotherapy dose via systemic administration actually reaches the tumorsite. In fact, even some of the most promising currently availablechemotherapies are not tolerable in the long term for most patients.

SUMMARY OF THE DISCLOSURE

Applicant has discovered an implantable and biodegradable drug deliverydevice capable of delivering an active pharmaceutical ingredient (API)directly to the target tissue in the patient. Since the drug deliverydevices disclosed herein utilize a local delivery method, these devicescan sidestep the problem of systemic side effects and can more directlyprovide site-specific treatment without having to perform subsequentremoval surgeries due to their biodegradable nature. Specifically, thedrug devices disclosed herein can be flexibly applied via open andminimally invasive surgery, allow for unidirectional, multidirectional,or omni-directional delivery of APIs via a multilayer configuration, actas a barrier to tumor ingrowth and prevent systemic drug leakage,provide tunable release profiles and degradation rates, and/or consentadaptable design translatable to a broad range of solid tumors.

The drug delivery devices can be flexible such that it can be placedonto target tissue (e.g., a peritumoral area of an organ) in a patientusing standard open, laparoscopic, endoscopic, percutaneous, or roboticsurgical equipment. In addition, the flexible drug delivery device canpliably conform with the underlying topography of the targeted tissuesite. In some embodiments, multiple drug delivery devices can be placedonto target tissue of a patient. In some embodiments, a second drugdelivery device can be placed onto target tissue of a patient after thefirst drug delivery device has already degraded.

Specifically, the drug delivery devices disclosed herein can include atleast two layers. One of the layers can include the API and abiodegradable polymer and a second layer can include anotherbiodegradable polymer that degrades slower than the first biodegradablepolymer. When the device is placed directly on tissue (i.e., when theAPI layer is facing the tissue), the API layer(s) can degrade therebyreleasing the API towards the target tissue. In some embodiments, thenon-API layer can prevent the API from being released away from thetarget tissue onto non-target tissue. In some embodiments, the non-APIlayer can prevent the drug delivery device from being released from thetarget tissue (i.e., the non-API layer can hold the drug delivery devicein place).

In some embodiments, the second layer can degrade more slowly than thefirst layer such that the second layer can continue to prevent the APIfrom being released away from the target tissue and/or retain the drugdelivery device on the target tissue site. As such, the second layer maynot degrade completely until the drug is completely released.Accordingly, the drug delivery device can be inserted in a patient totarget specific tissue without having to perform a subsequent surgery toremove the device as it is wholly or mostly absorbed by the patient'sbody.

The drug delivery devices disclosed herein can provide clinicallyrelevant delivery of an API directly to tissue (e.g., a tumor) with goodtolerance and minimal systemic exposure of the API. This device can beused as a neoadjuvant therapy (and/or adjuvant therapy) for treatment ofmany internal medical issues (e.g., cancer, other diseases, wounds,sores, lacerations, non-cancerous growths, etc.) that may improvecomplete resection rates, reduce the risk of local recurrence, and/orimprove survival of patients.

In some embodiments, a drug delivery device includes a first layercomprising an active pharmaceutical ingredient (API) and at least 70 wt.% of a first biodegradable polymer; and a second layer on a side of thefirst layer, the second layer comprising at least 80 wt. % of a secondbiodegradable polymer, wherein the second biodegradable polymer has aslower degradation rate than the first biodegradable polymer. In someembodiments, the drug delivery device includes a third layer between thefirst and second layer, wherein the third layer comprises an API and atleast 70 wt. % of a third biodegradable polymer. In some embodiments,the third biodegradable polymer has a slower degradation rate than thefirst biodegradable polymer. In some embodiments, the thirdbiodegradable polymer is the same as the first biodegradable polymer. Insome embodiments, the drug delivery device includes a fourth layer on aside of the second layer opposite the first layer, wherein the fourthlayer (with or without API) comprises at least 80 wt. % of a fourthbiodegradable polymer. In some embodiments, the fourth biodegradablepolymer has a slower degradation rate than the second biodegradablepolymer. In some embodiments, the fourth biodegradable polymer is thesame as the second biodegradable polymer. In some embodiments, an outerperimeter of the first layer is inset relative to an outer perimeter ofthe second layer such that a portion of the second layer extends beyondthe first layer. In some embodiments, the portion of the second layerextends beyond the first layer by 1-5 mm. In some embodiments, theportion of the second layer that extends beyond the first layercomprises an orientation identifier. In some embodiments, the firstbiodegradable polymer is poly(lactic-co-glycolic acid) (PLGA) 50:50. Insome embodiments, the second biodegradable polymer is PLGA 75:25. Insome embodiments, the first layer comprises 1-15 wt. % API. In someembodiments, the first layer comprises a solvent. In some embodiments,the first layer comprises 1-15 wt. % solvent. In some embodiments, thesolvent is acetone. In some embodiments, the second layer comprises asolvent. In some embodiments, the second layer comprises 1-15 wt. %solvent. In some embodiments, the API is paclitaxel. In someembodiments, the average thickness of the drug delivery device is100-1500 microns. In some embodiments, the drug delivery device isflexible such that it can be implanted in a patient using standard openand minimally invasive procedures. In some embodiments, the drugdelivery device is configured to be rolled to fit through a 3-12 mmtrocar. In some embodiments, the solvent is acetone.

In some embodiments, a method of preparing a drug delivery deviceincludes adding a first solution comprising a first biodegradablepolymer, an active pharmaceutical ingredient (API), and a solvent to amold; drying the first solution in the mold to form a first layer;adding a second solution comprising a second biodegradable polymer and asolvent over the first layer in the mold, wherein the secondbiodegradable polymer degrades slower than the first biodegradablepolymer; drying the second solution in the mold to form a second layeron a side of the first layer; and removing the multi-layered drugdelivery device from the mold. In some embodiments, the method includesheating the multi-layered drug delivery device in an oven after removingfrom the mold. In some embodiments, the multi-layered drug deliverydevice is in the oven at 35-45° C. for 2-4 days. In some embodiments,the method includes marking the second layer of the multi-layered drugdelivery device with an orientation identifier. In some embodiments, themethod includes sterilizing the drug delivery device. In someembodiments, sealing the multi-layered drug delivery device in a pouch.In some embodiments, an outer perimeter of the first layer is insetrelative to an outer perimeter of the second layer such that a portionof the second layer extends beyond the first layer. In some embodiments,the portion of the second layer extends beyond the first layer by 1-5mm. In some embodiments, the first biodegradable polymer ispoly(lactic-co-glycolic acid) (PLGA) 50:50. In some embodiments, thesecond biodegradable polymer is PLGA 75:25. In some embodiments, thefirst layer comprises 1-15 wt. % API. In some embodiments, the firstlayer comprises a solvent. In some embodiments, the first layercomprises 1-15 wt. % solvent. In some embodiments, the solvent isacetone. In some embodiments, the second layer comprises a solvent. Insome embodiments, the second layer comprises 1-15 wt. % solvent. In someembodiments, the solvent is acetone. In some embodiments, the API ispaclitaxel. In some embodiments, the average thickness of the drugdelivery device is 100-1500 microns. In some embodiments, the methodincludes before adding and drying the second solution in the mold toform the second layer, adding a third solution comprising a thirdbiodegradable polymer, an active pharmaceutical ingredient (API), and asolvent over the first layer in the mold and drying the third solutionin the mold to form a third layer between the first and second layers.In some embodiments, the method includes adding a fourth solutioncomprising a fourth biodegradable polymer and solvent (with or withoutAPI) over the second layer in the mold and drying the fourth solution inthe mold to form a fourth layer on a side of the second layer.

In some embodiments, a method of treating tissue of a patient includesimplanting a drug delivery device onto a target tissue site of apatient, the device comprising: a first layer comprising an activepharmaceutical ingredient (API) and at least 70 wt. % of a firstbiodegradable polymer; and a second layer on a side of the first layer,the second layer comprising at least 80 wt. % of a second biodegradablepolymer, wherein the second biodegradable polymer has a slowerdegradation rate than the first biodegradable polymer, wherein the drugdelivery device is implanted such that the first layer is facing towardsthe target tissue site; and releasing the API from the first layer tothe target tissue site, wherein the release of the API is controlled byin vivo degradation of the first biodegradable polymer at the targettissue site. In some embodiments, implanting the drug delivery devicecomprises suturing the drug delivery device to the target tissue site oran area around the target tissue site. In some embodiments, the secondlayer is sutured to the target tissue site or an area around the targettissue site. In some embodiments, the target tissue site is aperitumoral area of the pancreas, biliary system, gallbladder,esophageal system, liver, stomach, peritoneum, small bowel, lung, colon,or metastasis from a primary tumor. In some embodiments, the drugdelivery device is implanted such that the first layer is in directcontact with the target tissue site. In some embodiments, the firstlayer completely degrades within a period of 1 week to 10 months afterimplantation. In some embodiments, the second layer completely degradeswithin a period of 2 weeks to 1 year after implantation. In someembodiments, the release rate of the API is 1-10 mg/day. In someembodiments, the drug delivery device is implanted via open surgery,laparoscopically, robotically, endoscopically, or percutaneously. Insome embodiments, the drug delivery device is folded to fit through atrocar prior implantation. In some embodiments, the second layer isconfigured to prevent API leakage away from the target tissue site. Insome embodiments, the drug delivery device is used as a neoadjuvanttherapy. In some embodiments, the release of the API follows a delayperiod of about 1-14 days after implantation. In some embodiments, asub-therapeutically effective amount of the API is released during thedelay period. In some embodiments, releasing the API from the firstlayer to the target tissue site comprises releasing the APIunidirectionally, multi-directionally, or omnidirectionally away fromthe second layer.

Additional advantages will be readily apparent to those skilled in theart from the following detailed description. The examples anddescriptions herein are to be regarded as illustrative in nature and notrestrictive.

All publications, including patent documents, scientific articles anddatabases, referred to in this application are incorporated by referencein their entirety for all purposes to the same extent as if eachindividual publication were individually incorporated by reference. If adefinition set forth herein is contrary to or otherwise inconsistentwith a definition set forth in the patents, applications, publishedapplications and other publications that are herein incorporated byreference, the definition set forth herein prevails over the definitionthat is incorporated herein by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described, by way of example only, withreference to the accompanying drawings.

FIG. 1 illustrates a drug delivery device in accordance with someembodiments disclosed herein.

FIG. 2 illustrates an image of a drug delivery device showing theportion of the non-API layer that extends beyond the API layer inaccordance with some embodiments disclosed herein.

FIG. 3A illustrates an image of film 1 disclosed herein before oventesting.

FIG. 3B illustrates an image of film 1 disclosed herein prepared foroven testing.

FIG. 3C illustrates an image of film 1 disclosed herein after 20 minutesin a 45° C. oven testing.

FIG. 4A illustrates an image of film 2 disclosed herein before oventesting.

FIG. 4B illustrates an image of film 2 disclosed herein prepared foroven testing.

FIG. 4C illustrates an image of film 2 disclosed herein after 20 minutesat 42° C. oven testing.

FIG. 5A illustrates an image of film 3 disclosed herein before oventesting.

FIG. 5B illustrates an image of film 3 disclosed herein prepared foroven testing.

FIG. 5C illustrates an image of film 3 disclosed herein after 20 minutesin a 37° C. oven testing.

FIG. 6A illustrates an image of film 4 disclosed herein before oventesting.

FIG. 6B illustrates an image of film 4 disclosed herein prepared foroven testing.

FIG. 6C illustrates an image of film 4 disclosed herein after 20 minutesat room temperature testing.

FIG. 7A illustrates an image of film 5 disclosed herein before oventesting.

FIG. 7B illustrates an image of film 5 disclosed herein prepared foroven testing.

FIG. 7C illustrates an image of film 5 disclosed herein after 20 minutesat 40° C. oven testing.

FIG. 8A illustrates an image of film 6 disclosed herein before oventesting.

FIG. 8B illustrates an image of film 6 disclosed herein prepared foroven testing.

FIG. 8C illustrates an image of film 6 disclosed herein after 20 minutesat 40° C. oven testing.

FIG. 9A illustrates an image of film 6 disclosed herein prepared for itssecond oven testing.

FIG. 9B illustrates an image of film 6 disclosed herein after 20 minutesat 42° C. for its second oven testing.

FIG. 10A illustrates an image of film 6 disclosed herein prepared forits third oven testing.

FIG. 10B illustrates an image of film 6 disclosed herein after 20minutes at 45° C. for its third oven testing.

FIG. 11A illustrates an image of a drug delivery device showing theorientation identifier in accordance with some embodiments disclosedherein.

FIG. 11B a drug delivery device properly (left with check mark) andimproperly (right with X) oriented in accordance with some embodimentsdisclosed herein.

FIG. 12 illustrates another view of a drug delivery device in accordancewith some embodiments disclosed herein.

FIG. 13A illustrates locations (X) for attaching sutures (e.g.,fixation/cardinal sutures) to a drug delivery device in accordance withsome embodiments disclosed herein.

FIG. 13B illustrates an image of a drug delivery device with suturesattached ready to be implanted in accordance with some embodimentsdisclosed herein.

FIG. 14A illustrates an example location ([0]) for attaching anorientation identifying suture (e.g., prolene suture) to a drug deliverydevice in accordance with some embodiments disclosed herein.

FIG. 14B illustrates an image of a drug delivery device with anorientation identifying suture (e.g., prolene suture) in accordance withsome embodiments disclosed herein.

FIG. 15A illustrates a rolled up drug delivery device for implantationin accordance with some embodiments disclosed herein.

FIG. 15B illustrates an image of a rolled up drug delivery device forimplantation in accordance with some embodiments disclosed herein.

FIG. 15C illustrates another image of a rolled up drug delivery devicefor implantation in accordance with some embodiments disclosed herein.

FIG. 15D illustrates an image of a rolled up drug delivery device in atrocar for implantation in accordance with some embodiments disclosedherein.

FIG. 16A illustrates proper orientation of a drug delivery device withprolene suture (O) clockwise from fixation/cardinal suture X inaccordance with some embodiments disclosed herein.

FIG. 16B illustrates improper orientation of a drug delivery device withprolene suture (O) counter clockwise from fixation/cardinal suture X inaccordance with some embodiments disclosed herein.

FIG. 17 illustrates an example of a drug delivery device sutured inplace in accordance with some embodiments disclosed herein.

FIG. 18A illustrates the thickness measured at 3 different points on afirst example film before refrigeration in accordance with someembodiments disclosed herein.

FIG. 18B illustrates the thickness measured at 3 different points on asecond example film before refrigeration in accordance with someembodiments disclosed herein.

FIG. 18C illustrates the thickness measured at 3 different points onthird example film after 4 weeks of refrigeration in accordance withsome embodiments disclosed herein.

FIG. 18D illustrates the thickness measured at 3 different points on afourth example film after 11 weeks refrigeration in accordance with someembodiments disclosed herein.

FIG. 19 illustrates the average thickness for the four example filmsmeasured in accordance with some embodiments disclosed herein.

FIG. 20A illustrates the diameters for the four example films measuredin accordance with some embodiments disclosed herein.

FIG. 20B illustrates the average diameters for the four example filmsmeasured in accordance with some embodiments disclosed herein.

FIG. 21A illustrates the thicknesses of the three samples measured dryvs. wet in accordance with some embodiments disclosed herein.

FIG. 21B illustrates the diameters of the three samples measured dry vs.wet in accordance with some embodiments disclosed herein.

FIG. 22 illustrates a fluorescent viewed drug delivery device under aconfocal microscope in accordance with some embodiments disclosedherein.

FIG. 23A illustrates the degradation of a sample film after 1 day in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23B illustrates the degradation of a sample film after 3 days in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23C illustrates the degradation of a sample film after 5 days in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23D illustrates the degradation of a sample film after 7 days in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23E illustrates the degradation of a sample film after 2 weeks in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23F illustrates the degradation of a sample film after 3 weeks in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23G illustrates the degradation of a sample film after 4 weeks in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23H illustrates the degradation of a sample film after 6 weeks in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23I illustrates the degradation of a sample film after 8 weeks in abuffer solution in accordance with some embodiments disclosed herein.

FIG. 23J illustrates the degradation of a sample film after 10 weeks ina buffer solution in accordance with some embodiments disclosed herein.

FIG. 24 illustrates a graph of percent mass remaining over time (drymass/initial mass*100) for the samples tested for degradation rate inaccordance with some embodiments disclosed herein.

FIG. 25 illustrates a graph of percent of water absorbed by the discover time ((wet mass−dry mass)/dry mass*100) for the samples tested fordegradation rate in accordance with some embodiments disclosed herein.

FIG. 26 illustrates an exemplary flowchart of how the drug deliverydevice can attack tumor cells in accordance with some embodimentsdisclosed herein. Specifically, an eluting layer can degrade and releasedrugs within the tumor (left arrow sequence) and then the backing layercan degrade (right arrow sequence).

FIG. 27A illustrates an image of a drug delivery device implanted on aporcine abdominal wall in accordance with some embodiments disclosedherein.

FIG. 27B illustrates an image of a drug delivery device implanted on aporcine pancreas in accordance with some embodiments disclosed herein.

FIG. 28 illustrates the weight gain from the porcine studies inaccordance with some embodiments disclosed herein. Animals with implantson just the abdominal wall (left) and on both the pancreas and abdominalwall (right) gained weight over the 30 day period. A body condition ofthree indicates normal condition: Tube shape with slight rounding of thesides; Ribs, hips and backbone palpated with firm pressure.

FIG. 29 illustrates the histology of the abdominal wall from the porcinestudies in accordance with some embodiments disclosed herein. Abdominalwall underlying shows only mild hemorrhage (arrows) and necrosis inadipose tissue (asterisks).

FIG. 30 illustrates the histology of the pancreas from the porcinestudies in accordance with some embodiments disclosed herein. Lowmagnification view of pancreas and implant cross section (top) andhigher magnification views of boxed areas (bottom) showing a thincapsule and fibrosis.

FIG. 31 illustrates the drug accumulation in tissue after 30 days in theporcine studies showing drug primarily accumulates under the implant inaccordance with some embodiments disclosed herein.

FIG. 32A illustrates the weight of the drug delivery devices withoutoven drying or sterilization tested for drug release rates in accordancewith some embodiments disclosed herein.

FIG. 32B illustrates the cumulative drug release of drug deliverydevices without oven drying or sterilization tested in accordance withsome embodiments disclosed herein. Control is a single measurement—only1× measurement per disc.

FIG. 33 illustrates the cumulative drug release of oven dried andsterilized drug delivery devices in accordance with some embodimentsdisclosed herein.

FIG. 34 illustrates cumulative drug release of a single drug deliverydevice with oven drying but no sterilization in accordance with someembodiments disclosed herein.

FIG. 35A illustrates a graph of the tumor's largest dimension in a firstpatient over time from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 35B illustrates the tumor assessment from the first patient from aclinical trial of a drug delivery device in accordance with someembodiments disclosed herein.

FIG. 36A illustrates a radiographical image from the tumor as dashedline of the first patient at baseline from a clinical trial of a drugdelivery device in accordance with some embodiments disclosed herein.

FIG. 36B illustrates a 3D rendering of the tumor of the first patient atbaseline from a clinical trial of a drug delivery device in accordancewith some embodiments disclosed herein.

FIG. 37A illustrates a radiographical image from the tumor as dashedline of the first patient after 2 weeks post-implant pre-chemotherapyfrom a clinical trial of a drug delivery device in accordance with someembodiments disclosed herein.

FIG. 37B illustrates a 3D rendering of the tumor of the first patient at2 weeks post-implant pre-chemotherapy from a clinical trial of a drugdelivery device in accordance with some embodiments disclosed herein.

FIG. 38A illustrates a radiographical image from the tumor as dashedline of the first patient after 10 weeks post-implant pre cycle 5 ofchemotherapy from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 38B illustrates a 3D rendering of the tumor of the first patient at10 weeks post-implant pre cycle 5 of chemotherapy from a clinical trialof a drug delivery device in accordance with some embodiments disclosedherein.

FIG. 39A illustrates a radiographical image from the tumor as dashedline of the first patient after 16 weeks post-implant pre cycle 9 ofchemotherapy from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 39B illustrates a 3D rendering of the tumor of the first patient at16 weeks post-implant pre cycle 9 of chemotherapy from a clinical trialof a drug delivery device in accordance with some embodiments disclosedherein.

FIG. 40A illustrates a radiographical image from the tumor as dashedline of the first patient after 24 weeks post-implant pre cycle 12 ofchemotherapy from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 40B illustrates a 3D rendering of the tumor of the first patient at24 weeks post-implant pre cycle 12 of chemotherapy from a clinical trialof a drug delivery device in accordance with some embodiments disclosedherein.

FIG. 41A illustrates a graph of the tumor's largest dimension in asecond patient over time from a clinical trial of a drug delivery devicein accordance with some embodiments disclosed herein.

FIG. 41B illustrates the tumor assessment from the second patient from aclinical trial of a drug delivery device in accordance with someembodiments disclosed herein.

FIG. 42A illustrates a radiographical image from the tumor as dashedline of the second patient at baseline from a clinical trial of a drugdelivery device in accordance with some embodiments disclosed herein.

FIG. 42B illustrates a 3D rendering of the tumor of the second patientat baseline from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 43A illustrates a radiographical image from the tumor as dashedline of the second patient after 2 weeks post-implant from a clinicaltrial of a drug delivery device in accordance with some embodimentsdisclosed herein.

FIG. 43B illustrates a 3D rendering of the tumor of the second patientat 2 weeks post-implant from a clinical trial of a drug delivery devicein accordance with some embodiments disclosed herein.

FIG. 44A illustrates a radiographical image from the tumor as dashedline of the second patient after 10 weeks post-implant pre cycle 5 ofchemotherapy from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 44B illustrates a 3D rendering of the tumor of the second patientat 10 weeks post-implant pre cycle 5 of chemotherapy from a clinicaltrial of a drug delivery device in accordance with some embodimentsdisclosed herein.

FIG. 45A illustrates a radiographical image from the tumor as dashedline of the second patient after 16 weeks post-implant pre cycle 9 ofchemotherapy from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 45B illustrates a 3D rendering of the tumor of the second patientat 16 weeks post-implant pre cycle 9 of chemotherapy from a clinicaltrial of a drug delivery device in accordance with some embodimentsdisclosed herein.

FIG. 46A illustrates a graph of the tumor's largest dimension in a thirdpatient over time from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 46B illustrates the tumor assessment from the third patient from aclinical trial of a drug delivery device in accordance with someembodiments disclosed herein.

FIG. 47A illustrates a radiographical image from the tumor as dashedline of the third patient at baseline from a clinical trial of a drugdelivery device in accordance with some embodiments disclosed herein.

FIG. 47B illustrates a 3D rendering of the tumor of the third patient atbaseline from a clinical trial of a drug delivery device in accordancewith some embodiments disclosed herein.

FIG. 48A illustrates a radiographical image from the tumor as dashedline of the third patient after 2 weeks post-implant from a clinicaltrial of a drug delivery device in accordance with some embodimentsdisclosed herein.

FIG. 48B illustrates a 3D rendering of the tumor of the third patient at2 weeks post-implant from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 49A illustrates a radiographical image from the tumor as dashedline of the third patient after 10 weeks post-implant pre cycle 5 ofchemotherapy from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 49B illustrates a 3D rendering of the tumor of the third patient at10 weeks post-implant pre cycle 5 of chemotherapy from a clinical trialof a drug delivery device in accordance with some embodiments disclosedherein.

FIG. 50A illustrates a radiographical image from the tumor as dashedline of the third patient after 16 weeks post-implant pre cycle 9 ofchemotherapy from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 50B illustrates a 3D rendering of the tumor of the third patient at16 weeks post-implant pre cycle 9 of chemotherapy from a clinical trialof a drug delivery device in accordance with some embodiments disclosedherein.

FIG. 51A illustrates a radiographical image from the tumor as dashedline of the third patient after 24 weeks post-implant pre cycle 12 ofchemotherapy from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 51B illustrates a 3D rendering of the tumor of the third patient at24 weeks post-implant pre cycle 12 of chemotherapy from a clinical trialof a drug delivery device in accordance with some embodiments disclosedherein.

FIG. 52 illustrates the overall procedure time for implanting a drugdelivery device in accordance with some embodiments disclosed herein.

FIG. 53 illustrates the reduction in tumor size of the first patientfrom a clinical trial of a drug delivery device in accordance with someembodiments disclosed herein.

FIG. 54 illustrates tumor volumetric reduction of the three patientsfrom a clinical trial of a drug delivery device in accordance with someembodiments disclosed herein.

FIG. 55 illustrates tumor anterior/posterior reduction of the threepatients from a clinical trial of a drug delivery device in accordancewith some embodiments disclosed herein.

FIG. 56A illustrates a chart of the amount of CA 19-9 in the threepatients' blood from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

FIG. 56B illustrates a table of the amount of CA 19-9 in the threepatients' blood from a clinical trial of a drug delivery device inaccordance with some embodiments disclosed herein.

In the Figures, like reference numbers correspond to like componentsunless otherwise stated.

DETAILED DESCRIPTION OF THE DISCLOSURE

Described herein are exemplary embodiments of biodegradable drugdelivery devices that can be implanted in a patient to locally deliver acontrolled therapeutically effective amount of an API. Specifically, thedrug delivery devices disclosed herein can be configured to providecontrolled release of a therapeutically effective amount of an APIdirectly to a target tissue site (e.g., a tumor) by in vivo degradationof a biodegradable polymer layer containing the API.

In some embodiments, the drug delivery device can be a film or patchhaving multiple biodegradable layers. In some embodiments, the drugdelivery device can include at least one biodegradable layer. At leastone layer can include an API which can be released in vivo by polymerbiodegradation. In some embodiments, a second layer can be free of anyAPI. This non-API layer can be on a side of an API layer and prevent anyAPI from being released toward the non-API layer. In other words, thenon-API layer can help ensure that the API from the API layer during invivo degradation is being released away from the non-API backing layertowards the targeted tissue, not toward non-targeted tissue. Inaddition, this non-API layer can hold the drug delivery device in placeduring the degradation of the API layer. In some embodiments, thetargeted tissue can be cancerous tissue/cells or peritumoraltissue/cells on an organ. For example, the targeted tissue can becancerous or peritumoral tissue/cells on a pancreas, biliary system,gallbladder, esophageal system, liver, stomach, peritoneum, small bowel,lung, colon, or metastasis from a primary tumor.

FIG. 1 illustrates drug delivery device 100 that includes API layer 101and non-API backing layer 102. The API-containing layer can include API103 embedded within and/or on the surface of API layer 101. In use, theAPI layer would face the targeted tissue such that the API is releasedtoward the targeted tissue during degradation as shown by the arrows inFIG. 1 . Non-API backing layer 102 can prevent API from being releasedaway from the targeted tissue onto non-targeted tissue.

Although FIG. 1 illustrates the drug delivery device as a disc, the drugdelivery devices disclosed herein can come in many shapes, sizes, andgeometries. In some embodiments, the drug delivery device can becircular, square, rectangular, oval, triangular, diamond shaped, polygonshaped (e.g., pentagon, hexagon, octagon, etc.), arced, trapezoidal,star shaped, or a variety of other shapes and sizes. In someembodiments, the drug delivery device can be tubular, cylindrical, coneshaped, pyramidal, triangular prism shaped, cube shaped, spherical,rectangular prism shaped, or a variety of other shapes and sizes.

In some embodiments, the drug delivery devices can be made by a solventcasting method. As described in more detail below, at least onebiodegradable polymer and at least one API can be dissolved in a solventand cast in a mold. When dry, a second layer having at least onebiodegradable polymer can be cast on top of the first layer and thendried to form the device. This process can be repeated for as manyadditional API and/or non-API layers as necessary. In some embodiments,the drug delivery device can be made via a continuous process. In someembodiments, the drug delivery devices disclosed herein can be made bycontinuous processes such as those employed by the polymer filmproduction industry (e.g., extrusion, continuous film evaporation,etc.).

API Layer

In some embodiments, a drug delivery device can include at least one APIcontaining layer. In some embodiments, an API layer can include at leastone active pharmaceutical ingredient (API) and at least onebiodegradable polymer. In some embodiments, an API layer can includemore than one API. As explained above, an API layer can be configured toprovide controlled release of the API by in vivo degradation of thebiodegradable polymer at the target tissue site. In some embodiments, anAPI layer can also include one or more pharmaceutically acceptableexcipients.

In some embodiments, the biodegradable polymer can be any suitablebiodegradable polymer known in the art. For example, the biodegradablepolymers can include synthetic polymers selected from poly(amides),poly(esters), poly(anhydrides), poly(orthoesters), polyphosphazenes,pseudo poly(amino acids), poly(glycerol-sebacate), copolymers thereof,and mixtures thereof. In addition, the biodegradable polymers may beformed from poly(lactic acids), poly(glycolic acids),poly(lactic-co-glycolic acids), poly(caprolactones), and mixturesthereof. In some embodiments, the biodegradable polymer can bepoly(lactic-co-glycolic acid) (PLGA). In some embodiments, the PLGA canbe PLGA with various lactic acid to glycolic acid ratios such as PLGA50:50, PLGA 60:40, PLGA 65:35, PLGA 70:30, PLGA 75:25, PLGA 80:20, PLGA85:15, PLGA 90:10, or other various ratios of PLGA. In some embodiments,the biodegradable polymer in an API containing layer includes PLGA50:50. In some embodiments, the PLGA 50:50 can be Resomer 504H fromEvonik.

PLGA can undergo degradation by hydrolysis or biodegradation throughcleavage of its backbone ester linkages into oligomers followed bymonomers. The lactide-glycolide ratio dictates the degradation rate ofthe PLGA in aqueous media (e.g., water and water containing environmentssuch as inside a human or animal's anatomy). In general, the higherlactic acid content or lactide content, the lower the degradationbehavior of the PLGA as lactide has hydrophobic properties which canprevent water from hydrolyzing the ester bonds in PLGA. As such, PLGA50:50 degrades faster in water-containing environments than PLGA 65:35,which degrades faster than PLGA 75:25.

In some embodiments, an API containing layer includes at least about 50wt. %, at least about 60 wt. %, at least about 70 wt. %, at least about73 wt. %, at least about 75 wt. %, at least about 80 wt. %, at leastabout 85 wt. %, or at least about 90 wt. % biodegradable polymer. Insome embodiments, an API containing layer includes at most about 95 wt.%, at most about 90 wt %, at most about 85 wt. %, at most about 80 wt.%, at most about 77 wt. %, or at most about 75 wt. % biodegradablepolymer. In some embodiments, an API containing layer includes about60-95 wt. %, about 70-95 wt. %, about 75-90 wt. %, about 75-89 wt. %, orabout 79-89 wt. % biodegradable polymer.

In some embodiments, the API may be an active pharmaceutical ingredientfor the treatment of human or veterinary diseases. APIs may be one ormore of antibacterial agents, antifungal agents, antiprotozoal agents,antiviral agents, labor-inducing agents, spermicidal agents,prostaglandins, steroids and microbicides, proteins/peptides and vaccineantigens.

Suitable APIs include, without limitation: analgesics andanti-inflammatory agents (e.g., ibuprofen), antacids, anthelmintics,anti-arrhythmic agents, anti-bacterial agents, anti-coagulants,anti-anxiety anti-depressants, anti-diabetics, anti-diarrhoeals,anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensiveagents, anti-malarials, anti-migraine agents, anti-muscarinic agents,anti-neoplastic agents and immunosuppressants, anti-protazoal agents,anti-rheumatics, anti-thyroid agents, antivirals, anxiolytics,sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropicagents, corticosteroids, cough suppressants, cytotoxics, decongestants,diuretics, enzymes, anti-parkinsonian agents, gastro-intestinal agents,histamine receptor antagonists, lipid regulating agents, localanesthetics, neuro muscular agents, nitrates and anti-anginal agents,nutritional agents, opioid analgesics, oral vaccines, proteins, peptidesand recombinant drugs, sex hormones and contraceptives, spermicides,stimulants, smoking cessation products and combinations thereof.

In some embodiments, the API can be a chemotherapeutic agent such as anydrug formulation effective to treat cancer by inhibiting the growth,invasiveness of malignant cells, and/or inducing cytotoxicity byapoptosis or necrosis of malignant cells. The chemotherapeutic agent canbe a taxane or platinum drug. In some embodiments, the chemotherapeuticagent includes an MEK inhibitor, a KRAS inhibitor, a PI3K inhibitor, aHedgehog inhibitor, a Wnt inhibitor, or a combination thereof. In someembodiments, the chemotherapeutic agent can interfere with the mTOR orNfKb pathways. In some embodiments, the chemotherapeutic agent includesSTING agonist compounds. In some embodiments, the chemotherapeutic agentcan interfere with the STING pathway. In some embodiments, thechemotherapeutic agent includes genetic material such as mRNA, siRNA,etc. In some embodiments, the chemotherapeutic agent can besiRNA-Alnylam type therapies.

In some embodiments, the API can include a vaccinal antigen. In someembodiments, the API can be an mRNA vaccinal antigen such as an mRNAcancer vaccinal antigen.

The API may be a single active pharmaceutical ingredient, such as asingle chemical entity, or it may be a mixture of several activepharmaceutical ingredients. The active pharmaceutical ingredient may beof any of the many categories of active pharmaceutical ingredients. Theactive pharmaceutical ingredient may be selected from, but is notlimited to, the group consisting of paclitaxel, gemcitabine,nab-paclitaxel, 5-fluorouracil, oxaliplatin, irinotecan, docetaxel,vinorelbine, etoposide, mitomycin-C, cisplatin/carboplatin,fluorouracil, methotrexate, TAS-102, or combinations thereof. In someembodiments, the API is paclitaxel. In some embodiments, the paclitaxelis from Phyton Biotech.

In some embodiments, the API can be an API for targeted therapy such asbevacizumab, ramucirumab, erlotinib, afatinib, gefitinib, osimertinib,dacomitinib, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib,dabrafenib, trametinib, sunitinib, regorafenib, or combinations thereof.In some embodiments, the API can be an API for immunotherapies such asnivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, orcombinations thereof.

In some embodiments, the API can be acyclovir, fluconazole, progesteroneand derivatives thereof, nonoxylenol-9, terbutaline, lidocaine,testosterone and derivatives, dinoprostone, lactobacillus, estrogen andderivatives, naphthalene2-sulfonate, lesmitidan, doxycycline, droxidopa,sapropterin, butoconazole, clindamycin nitrate/phosphate, neomycinesulfate, polymyxin sulfate, nystatin, clotrimazole, dextrin sulphate,glyminox, miconazole nitrate, benzalkonium chloride, sodium laurylsulphate, tenofovir, insulin, calcitonin, danazol, ibuprofen,acetaminophen, cefpodoxime proxetil, desloratadine, dextromethorphan,diphenhydramine hydrochloride, vitamins and/or minerals, adipic acid,ascorbic acid, macrolide antibiotics, NS-AIDS, cefuroxime axetil,amobarbital, ciprofloxacin hydrochloride, sildenafil citrate, pinaveriumbromide, propantheline bromide, triprolidine Hcl, dimenhydrinate,cefeanel daloxate HCl, Enoxacin, Sparfloxacin, aspirin, famotidine,amoxycilin trihydrate, morphine HCl, amiprilose HCl, terfenadine,beclamide, clarithromycin, roxithromycin, nizatidine, cetraxate HCl,ciprofloxacin, bifemelene HCl, Cefuroxime axetil, pirienzepine and/oroxyburynin, diclofenac, nicorandil, levofloxacin, acriflavine,leuprorelin acetate, metronidazole, benzydamine hydrochloride,chloramphenicol, oxybutynin, ethinyl estradiol, prostaglandins, insulin,calcitonin and combinations thereof. The active pharmaceuticalingredient may also be vaccine antigen such as those for the treatmentof Hepatitis B, HIV, HPV, Chlamydia, gonococcal infections.

APIs may include salts, esters, hydrates, solvates and derivatives ofany of the foregoing active ingredients. Suitable derivatives are thosethat are known to skilled persons to possess the same activity as theactive ingredient though the activity level may be lower or higher. Insome embodiments, the API can be in the form of microspheres. In someembodiments, the microspheres can release the API. In some embodiments,the API is encapsulated within microspheres.

When present, an API is employed in the formulation in a therapeuticallyeffective amount that is necessary to provide the dosage required,typically for producing at least one physiological effect as establishedby clinical studies. One of ordinary skill in the art can readilydetermine an appropriate amount of an active pharmaceutical ingredientto include in the drug delivery device made according to the presentdisclosure.

In some embodiments, an API containing layer includes at least about 1wt. %, at least about 2 wt. %, at least about 3 wt. %, at least about 5wt. %, at least about 7 wt. %, at least about 8 wt. %, at least about 9wt. %, at least about 10 wt. %, at least about 11 wt. %, or at leastabout 15 wt. % API. In some embodiments, an API containing layerincludes at most about 30 wt. %, at most about 20 wt. %, at most about15 wt. %, at most about 12 wt. %, at most about 11 wt. %, at most about10 wt. %, at most about 9 wt. %, at most about 8 wt. %, at most about 7wt. %, or at most about 5 wt. % API. In some embodiments, an APIcontaining layer includes about 1-15 wt. %, about 5-15 wt. %, about 7-12wt. %, about 8-12 wt. %, or about 7.5-11 wt. % API. In some embodiments,an API containing layer can include about 1-500 mg, about 25-450 mg,about 30-400 mg, about 40-350 mg, about 50-300 mg, about 60-250 mg,about 70-200 mg, about 80-150 mg, about 85-125 mg, about 90-105 mg,about 95-105 mg, or about 100 mg API.

To prepare an API layer in some embodiments of the drug delivery devicesdisclosed herein, a solution of a biodegradable polymer and an API canbe formed. Specifically, an amount of biodegradable polymer can bedissolved in a solvent. The biodegradable polymer/solvent solution canbe stirred and/or heated to help dissolve the polymer in the solvent. Insome embodiments, the solvent can be acetone, chloroform,tetrahydrofuran, ethyl acetate, methyl acetate, xylene, toluene, methylethyl ketone, methylene chloride, isopropyl alcohol, methyl isobutylketone, methyl propyl ketone, trichloroethylene, other substitutes foracetone, or combinations thereof. In some embodiments, the biodegradablepolymer and solvent solution can be about 0.1-0.3 g biodegradablepolymer, about 0.15-0.25 g biodegradable polymer, about 0.175-0.225 gbiodegradable polymer, about 0.19-0.21 g biodegradable polymer, about0.198-0.202 g biodegradable polymer, or about 0.2 g biodegradablepolymer per 1 mL solvent. In other words, 20 g biodegradable polymer in100 mL of solvent would be a biodegradable polymer and solvent solutionof 0.2 g biodegradable polymer per 1 mL solvent. The aboveconcentrations can also be true for the biodegradable polymer/APIsolution discussed below. For example, the biodegradable polymer/APIsolution can have about 0.1-0.3 g biodegradable polymer, about 0.15-0.25g biodegradable polymer, about 0.175-0.225 g biodegradable polymer,about 0.19-0.21 g biodegradable polymer, about 0.198-0.202 gbiodegradable polymer, or about 0.2 g biodegradable polymer per 1 mLsolvent.

After the biodegradable polymer is dissolved in the solvent, the API canbe added to the solution. In some embodiments, the API and biodegradablepolymer can be added simultaneously to the solvent. In some embodiments,the API can be added to the solvent prior to the addition of thebiodegradable polymer. In some embodiments, the API can be added to asolvent to form a first solution, the biodegradable polymer can be addedto a solvent to form a second solution, and the first and secondsolutions can be combined to form the biodegradable polymer/APIsolution. In some embodiments, the API can be in the form ofmicrospheres when incorporating the API to a biodegradable polymerlayer. In some embodiments, the microspheres can help prevent the APIfrom dissolving and/or deteriorating in the polymer/solvent solution.

In some embodiments, the biodegradable polymer/API solution can haveabout 0.01-0.05 g API, about 0.01-0.04 g API, about 0.015-0.035 g API,about 0.02-0.03 g API, about 0.023-0.027 g API, or about 0.025 g API per1 mL solvent. The above concentrations are also true for an API andsolvent solution (without the biodegradable polymer). The biodegradablepolymer/API solution can be stirred and/or heated until the API is wellmixed and/or dissolved in the solvent.

After the biodegradable polymer/API solution is formed, the solution canbe added to a mold. The mold can be any container used to give shape tothe API layer when it is formed. As such, the mold can be circular,square, rectangular, oval, triangular, diamond shaped, polygon shaped(e.g., pentagon, hexagon, octagon, etc.), arced, trapezoidal, starshaped, or a variety of other shapes and sizes. Besides shape, the moldcan also dictate the size (i.e., width, length, diameter, etc.) of thelayer.

Accordingly, if the drug delivery device is to be circular in shape, thebiodegradable polymer/API solution can be added to a circular mold. Insome embodiments, the mold can be an evaporation dish, a petri dish, orthe like. In addition, the amount added to the mold can depend on thedesired thickness and/or API concentration of the API layer. Inaddition, the amount added to the mold can depend on the desired APIrelease rate of the API layer. In some embodiments, about 1-20 mL, about1-10 mL, about 4-6 mL, or about 5 mL of the biodegradable polymer/APIsolution can be added to the mold.

Once in the mold, biodegradable polymer/API solution can be dried. Thisdrying can cause solvent to evaporate, thereby leaving a solidifiedlayer that includes biodegradable polymer, API, and some remainingsolvent. Remaining solvent in the layer can be important because itallows the layer(s) to retain flexibility and not crack duringsubsequent folding/rolling. As such, an API layer can also include asmall amount of solvent, which will be discussed in further detailbelow. In some embodiments, the biodegradable polymer/API solution canbe dried in air, nitrogen, or other gases at room temperature (e.g.,20-25° C.) in the mold. In some embodiments, the biodegradablepolymer/API solution can be dried in an environment with a humidity ofless than about 30%, less than about 25%, less than about 20%, less thanabout 15%, less than about 10%, less than about 5%, or less than 1%. Insome embodiments, the drying can be for about 1-6 days, about 1-4 days,about 1-3 days, or about 1.5-2.5 days.

Non-API Layer

In some embodiments, a drug delivery device can include at least onenon-API containing layer. In some embodiments, a non-API layer can befree from an API. In some embodiments, the non-API layer can include atleast one biodegradable polymer. As explained above, in someembodiments, a non-API layer can act as a backing layer to an API layerand can help prevent the API from being released away from the targettissue site onto non-targeted tissue. In some embodiments, the non-APIlayer can include a biodegradable polymer with a slower degradation ratethan the biodegradable polymer in an API layer. As explained below, PLGA50:50 can be the biodegradable polymer in the API layer and PLGA 75:25can be the biodegradable polymer in the second layer as PLGA 75:25degrades slower than the PLGA 50:50. In some embodiments, the non-APIlayer can include a biodegradable polymer with the same or fasterdegradation rate than the biodegradable polymer in an API layer. In someembodiments, a non-API layer can also include one or morepharmaceutically acceptable excipients.

For example, the biodegradable polymer in the API layer can degrade overthe course of about 4 weeks releasing the API towards the targetedtissue. The biodegradable polymer in the non-API layer can degrade in alonger period of time (e.g., 10 weeks). Thus, in some embodiments, thenon-API backing layer can be used to hold the drug delivery device inits targeted location (e.g., on a tumor) while the API layer degrades torelease the API. After the API layer completely degrades and the API hasbeen completely released to the targeted tissue, the non-API layer cancompletely degrade to be absorbed by the body of the patient. In someembodiments, a portion of the non-API layer can degrade while the APIlayer is degrading, but the degradation rate of the non-API layer can beslower than the API layer's degradation rate such that the non-API layercan prevent any API from being released away from the target tissue siteand/or hold the drug delivery device into place at the target tissuesite. Thus, in some embodiments, the non-API layer allows forunidirectional delivery of the API towards the target tissue site.

In some embodiments, the biodegradable polymer can be any suitablebiodegradable polymer known in the art. As explained above, abiodegradable polymer in a non-API layer has a slower degradation ratethan a biodegradable polymer in the API layer. For example, thebiodegradable polymers can include synthetic polymers selected frompoly(amides), poly(esters), poly(anhydrides), poly(orthoesters),polyphosphazenes, pseudo poly(amino acids), poly(glycerol-sebacate),copolymers thereof, and mixtures thereof. In addition, the biodegradablepolymers may be formed from poly(lactic acids), poly(glycolic acids),poly(lactic-co-glycolic acids), poly(caprolactones), and mixturesthereof. In some embodiments, the biodegradable polymer can bepoly(lactic-co-glycolic acid) (PLGA). In some embodiments, the PLGA canbe PLGA with various lactic acid to glycolic acid ratios such as PLGA50:50, PLGA 60:40, PLGA 65:35, PLGA 70:30, PLGA 75:25, PLGA 80:20, PLGA85:15, PLGA 90:10, or other various ratios of PLGA. In some embodiments,the biodegradable polymer in a non-API containing layer includes PLGA75:25. In some embodiments, the PLGA 75:25 can be Resomer 756S fromEvonik.

In some embodiments, a non-API containing layer includes at least about70 wt. %, at least about 75 wt. %, at least about 80 wt. %, at leastabout 85 wt. %, at least about 90 wt. %, or at least about 95 wt. %biodegradable polymer. In some embodiments, a non-API containing layerincludes at most about 99.9 wt. %, at most about 99 wt. %, at most about98 wt %, at most about 97 wt. %, at most about 95 wt. %, or at mostabout 90 wt. % biodegradable polymer. In some embodiments, a non-APIcontaining layer includes about 80-99.9 wt. %, about 85-98 wt. %, about86-97 wt. %, or about 88-96 wt. % biodegradable polymer.

To prepare a non-API layer for the drug delivery device, a secondsolution of a biodegradable polymer can be formed. Specifically, anamount of biodegradable polymer can be dissolved in a solvent. Thesecond biodegradable polymer/solvent solution can be stirred and/orheated to help dissolve the polymer in the solvent. In some embodiments,the solvent can be acetone, chloroform, tetrahydrofuran, ethyl acetate,methyl acetate, xylene, toluene, methyl ethyl ketone, methylenechloride, isopropyl alcohol, methyl isobutyl ketone, methyl propylketone, trichloroethylene, other substitutes for acetone, orcombinations thereof. In some embodiments, the biodegradable polymer andsolvent solution can be about 0.1-0.3 g biodegradable polymer, about0.15-0.25 g biodegradable polymer, about 0.175-0.225 g biodegradablepolymer, about 0.19-0.21 g biodegradable polymer, about 0.198-0.202 gbiodegradable polymer, or about 0.2 g biodegradable polymer per 1 mLsolvent. In other words, 20 g biodegradable polymer in 100 mL of solventwould be a biodegradable polymer and solvent solution of 0.2 gbiodegradable polymer per 1 mL solvent.

In some embodiments, after the second biodegradable polymer solution isformed, the solution can be added to the mold containing the API layer.As such, the second biodegradable polymer solution can be added over theAPI layer in the mold such as a covering or coating over the API layer.The amount added to the mold can depend on the desired thickness (anddegradation rate) of the non-API layer. In some embodiments, about 1-20mL, about 1-10 mL, about 4-6 mL, or about 5 mL of the biodegradablepolymer second solution can be added to the mold with the API layer. Insome embodiments, the non-API biodegradable solution can be added to themold first to form the non-API layer (in a similar manner to the APIlayer as explained above with respect to the API layer) and then an APIlayer can be formed on top of the non-API layer in the mold.

Once in the mold, second biodegradable polymer solution can be dried. Insome embodiments, this drying can cause solvent to evaporate, therebyleaving a second solidified layer on a side of the first solidified APIlayer. The second layer can be adhered to the first layer via a solventwelding process. In other words, the second layer can adhere to thefirst layer because the first layer may dissolve slightly when thesecond layer is applied and can redry with the second layer to form asolid second layer on a side of the solid first layer. This second layercan include biodegradable polymer (having a slower degradation rate thanthe biodegradable polymer of the first API layer) and some remainingsolvent. As such, a non-API layer can also include a small amount ofsolvent, which will be discussed in further detail below. In someembodiments, the non-API biodegradable polymer solution can be dried inair, nitrogen, or other gases at room temperature (e.g., 20-25° C.) inthe mold. In some embodiments, the non-API biodegradable polymersolution can be dried in an environment with a humidity of less thanabout 30%, less than about 25%, less than about 20%, less than about15%, less than about 10%, less than 5%, or less than about 1%. In someembodiments, the drying can be for about 1-6 days, about 1-4 days, about1-3 days, or about 1.5-2.5 days. The layers of the drug delivery devicecan have uniform consistency and be homogeneous.

The above process of preparing an API layer and a non-API layer adheredto the API layer can be repeated for additional layers as well as otherAPI layers and non-API layers adhered to a side of the API layer, otherAPI layers, the non-API layer, and/or other non-API layers. In otherwords, the drug delivery devices disclosed herein can include any numberof API layers and non-API layers in any order such as API/non-API,non-API/API, API/non-API/API, non-API/API/non-API, API/API/non-API,non-API/API/API, API/non-API/API/non-API, API/API/non-API/non-API,API/API/API/non-API, non-API/API/non-API/API, non-API/API/API/non-APIconfigurations and so on. These additional API layers and/or non-APIlayers can have a composition of any API layer or non-API layerdisclosed herein and be made by the same process as any API layer ornon-API layer disclosed herein.

In some embodiments, the drug delivery device can include more than oneAPI layer. In some embodiments, the drug delivery device can include anon-API layer sandwiched between two API layers. In some embodiments,the drug delivery device can include two API layers on top of oneanother and then a non-API layer on a side of one of the API layers. Forexample, in some embodiments, the drug delivery device can include asecond API layer on a side of the first API layer and a non-API layer ona side of the second API layer opposite the first API layer. In someembodiments, the second API layer can have the same composition (i.e.,API) as the first API layer. In some embodiments, there may be more thantwo API layers before a non-API layer. These API layers can have thesame or different composition or the same or different API. Furthermore,these additional layers can be added to the drug delivery device by thesame methods disclosed herein.

In some embodiments, the drug delivery device can include more than onenon-API layer. In some embodiments, the drug delivery device can includean API layer sandwiched between two non-API layers. For example, in someembodiments, the drug delivery device can include a first non-API layeron a side of the API layer and a second non-API layer on a side of theAPI layer opposite the first non-API layer. In some embodiments, thesecond non-API layer can have the same composition as the first non-APIlayer. In some embodiments, the second non-API layer can have adifferent composition as the first non-API layer. In some embodiments,the second non-API layer can degrade faster, slower, or the same as theAPI layer. In some embodiments, the first non-API layer can degradefaster, slower, or the same as the API layer. In some embodiments, firstnon-API layer can degrade faster, slower, or the same as the secondnon-API layer. In some embodiments, there may be more than two non-APIlayers before a API layer. Furthermore, these additional layers can beadded to the drug delivery device by the same methods disclosed herein.

In some embodiments, the drug delivery device can include a second APIlayer on a side of the first API layer configured to degrade at a slowerrate than the first API layer, and a non-API layer configured to degradeat a slower rate than the second API layer on side of the second APIlayer opposite the first API layer. In other words, a first solution ofa first biodegradable polymer and a first API can be added to a mold anddried to form a first layer. Next, a second solution of a secondbiodegradable polymer (having a degradation rate slower than the firstbiodegradable polymer) and a second API can be added over the firstlayer in the mold and dried to form a second layer. Next, a thirdsolution of a third biodegradable polymer (having a degradation rateslower than the second biodegradable polymer) can be added over thesecond layer in the mold and dried to form a third non-API layer. Forexample, the drug delivery device can include a first layer with an APIand PLGA 50:50, a second layer with the same or different API and PLGA65:35, and a non-API layer containing PLGA 75:25. The first PLGA 50:50layer would degrade first releasing the first API, then the second PLGA65:35 layer would degrade releasing the second API, and finally thenon-API PLGA 75:25 layer would degrade.

After the desired amount of API and non-API layers have been added anddried in the mold, the drug delivery film can be removed from the mold.In some embodiments, an outer perimeter of the first layer (e.g., an APIlayer) can be inset relative to an outer perimeter of a second layer(e.g., non-API layer) formed on top of the first layer such that aportion of the second layer extends beyond the first layer. This isshown in FIG. 2 which illustrates an image of a drug delivery devicehaving an API layer 101 and non-API layer 102, wherein a portion of thenon-API layer extends beyond the first layer acting as a border, rim, oredge 104 around the API layer.

There are many ways to form this border around the API layer. In someembodiments, because the composition (and viscosity) of the non-APIlayer is different from the API layer, the non-API layer can adhere andclimb the edges or sides of the mold (e.g., evaporation dish) when addedto the mold. Thus, during drying, a portion of the non-API layer canform on the edges or sides of the mold and not directly on the APIlayer. This portion that forms on the edges or sides of the mold can bethe border, rim, or edge shown around the API layer.

Oven Drying

Because the drug delivery devices disclosed herein can be placeddirectly onto target tissue areas using minimally invasive standardsurgical techniques such as open, laparoscopic, endoscopic,percutaneous, or robotic surgery, the drug delivery device should beflexible enough to be used with standard surgical equipment (e.g., atrocar used in laparoscopic surgery, a catheter in endoscopic surgery, abronchoscope, robotic bronchoscope, etc.). In some embodiments, the drugdelivery devices can be rolled and/or folded to be inserted through a 3mm to 12 mm (e.g., 3, 5, 8, 10, 12 mm trocar) and larger trocar. Thus,once inside the patient, the drug delivery device can be unfolded to beplaced onto the target tissue site (e.g., tumor) using standard surgicalequipment. In some embodiments, the drug delivery device is placed onthe target tissue such that it covers the targeted tissue and is adheredto tissue adjacent to the targeted tissue. For example, if the targetedtissue is a tumor of an organ, the drug delivery device can be placed onthe organ to cover the tumor area with the API layer (i.e., the APIlayer is in contact with the tumor or peritumoral area) of the drugdelivery device and the device can be adhered to non-tumor portions ofthe organ.

In initial studies, Applicant discovered that when some drug deliverydevices were inserted inside a patient, the high internal temperaturecaused the device to adhere to itself or melt or flow such that it couldnot be properly unfolded to be placed on the target tissue site.Applicant discovered that at least part of the cause of this was thatthere was too much solvent left in the drug delivery device. Solvent canbe important because it allows the layer(s) (and overall device) toretain flexibility and not crack during subsequent folding/rolling.However, too much solvent can cause the layer(s) to stick/adhere tothemselves at warm temperatures. Accordingly, Applicant discovered a wayto remove more solvent as well as a more optimal amount of solvent inthe drug delivery device for it to be properly implantable in a patient(i.e., maintain proper flexibility/pliability for surgery, but notadhere/stick to itself).

Specifically, six films containing a first layer of 0.8-1 g of PLGA50:50 (and acetone) and a second layer on a side of the first layer madeup of 0.8-1 g PLGA 75:25 (and acetone) were tested in an oven todetermine whether manufacturing changes effected the tendency of thefilms to adhere to themselves. Film 1 was rolled up and folded once, andthe shape was held in place using a rubber band while placed in an oven(HeraTherm high temp oven) for 20 minutes at 45° C. After 20 minutes,film 1 was completely adhered and could not be unrolled by any means asshown in FIGS. 3A-3C. Film 2 was rolled and folded in the same fashionas film 1 and placed in the oven for 20 minutes at 42° C. After 20minutes, Film 2 could still be unfolded, but was partially stuck atareas that were most tightly wrapped as shown in FIGS. 4A-4C. Films 3,4, and 5 were tested to confirm that the test results were consistentwith results obtained during method development. Film 3 was folded thesame way as previous tests, and placed in the oven at 37° C. for 20minutes, film 4 was similarly folded but held at room temperature for 20minutes, and film 5 was similarly folded and placed in the oven at 40°C. for 20 minutes. Film 3 could not be fully opened after 20 minutes at37° C. because some areas did adhere as shown in FIGS. 5A-5C. Thisoccurred at a lower temperature than was seen in previous batches. Film4 showed no signs of sticking as shown in FIGS. 6A-6C. Film 5 was fullyadhered and could not be opened at all as shown in FIGS. 7A-7C.

Film 6 was dried in a Binder Convection oven at 40° C. for 3 daysfollowing initial manufacture. Film 6 felt stiffer at room temperatureafter removal from the oven suggesting that there may have beenadditional solvent removal. Film 6 was rolled and folded and placed inan oven at 40° C. for 20 minutes. After removal, because it did notstick, film 6 was retested at 42° C. for 20 minutes and finally 45° C.for 20 minutes. Film 6 did not adhere to itself at all during any of thetests as shown in FIGS. 8A-8C, 9A-9B, and 10A-10B. As such, films thatwere not dried may not perform appropriately at temperatures that couldbe experienced when the drug delivery device is implanted inhuman/animal trials. However, Applicant discovered that the addition ofan oven drying step could remove enough excess solvent such that thedrug delivery device may not have performance issues even at 45° C., atemperature outside the range that would be expected clinically.

Accordingly, after removal of the drug delivery device from the mold (orin some embodiments while still in the mold), the drug delivery devicecan be placed in an oven for additional drying. In some embodiments, thedrug delivery device is placed in an oven at at least about 30° C., atleast about 35° C., at least about 36° C., at least about 37° C., atleast about 38° C., at least about 39° C., at least about 40° C., or atleast about 42° C. In some embodiments, the drug delivery device isplaced in an oven at at most about 50° C., at most about 45° C., at mostabout 42° C., at most about 40° C., at most about 39° C., at most about38° C., at most about 37° C., or at most about 36° C. In someembodiments, the drug delivery device is placed in an oven at 30-45° C.,32-45° C., 35-45° C., 35-42° C., 35-41° C., 36-40° C., 37-39° C., or 38°C. In some embodiments, the drug delivery device is placed in an ovenfor about 1-5 days, about 2-4 days, about 2.5-3.5 days, about 2.75-3.25days, about 68-80 hours, or about 3 days.

Thus, the drug delivery device can have a solvent content of less thanabout 12 wt. % or about 1-15 wt. %, about 2-12 wt %, or about 3-11 wt.%. In some embodiments, an API-layer of the drug delivery device canhave at least about 1 wt. %, at least about 2 wt. %, at least about 3wt. %, at least about 3.5 wt. %, at least about 5 wt. %, at least about7 wt. %, or at least about 10 wt. % solvent. In some embodiments, an APIlayer of the drug delivery device can have at most about 15 wt. %, atmost about 12 wt. %, at most about 10 wt. %, or at most about 5 wt. %solvent. In some embodiments, an API layer of the drug delivery devicecan have about 1-15 wt. %, about 2-12 wt %, about 3-11 wt. %, or about3.5-10 wt. % solvent. In some embodiments, a non-API layer of the drugdelivery device can have at least about 1 wt. %, at least about 2 wt. %,at least about 3 wt. %, at least about 3.5 wt. %, at least about 5 wt.%, at least about 7 wt. %, or at least about 10 wt. % solvent. In someembodiments, a non-API layer of the drug delivery device can have atmost about 15 wt. %, at most about 12 wt. %, at most about 11 wt. %, atmost about 10 wt. %, or at most about 5 wt. % solvent. In someembodiments, a non-API layer of the drug delivery device can have about1-15 wt. %, about 2-12 wt %, about 3-11 wt. %, or about 3.5-11 wt. %solvent. The amount of solvent in the drug delivery device can bemeasured by gas chromatography.

In some embodiments, the drug delivery device can be sterilized such asby e-beam radiation. In addition, the drug delivery device can be sealedin a pouch such as a Tyvek pouch to be sterilized and stored in afridge.

Orientation Indicator and Suturing

As explained above, an outer perimeter of an API layer can be insetrelative to an outer perimeter of a non-API layer such that a portion ofa non-API layer extends beyond the first layer as shown in FIG. 2 .Because the biodegradable polymers utilized in the layers can havesimilar colors and/or similar transparency, it can be difficult forsomeone to identify which side of the drug delivery device has the APIlayer and the non-API layer. As such, in some embodiments, a non-APIlayer can be marked with an orientation identifier. In some embodiments,the portion (i.e., the rim) of the non-API layer that extends beyond theAPI layer can include the orientation identifier. In some embodiments,an API layer can be marked with an orientation identifier. In someembodiments, the orientation identifier can be applied with a jewelrystamp. In some embodiments, there are more than one orientationidentifiers. These orientation identifiers can be applied at multiplelocations on the non-API or API layer. The orientation identifier can beany type of identification mark such as letter(s), number(s), words,images, shapes, etc. In some embodiments, the orientation identifier isa stamp on a layer. For example, FIG. 11A illustrates an image of a drugdelivery device showing the orientation identifier 105 (e.g., “PT”).Thus, a surgeon can identify the orientation identifier in the patientduring operation to know which side of the drug delivery device has thedrug containing layer. For example, when the API layer is oriented awayfrom the reader (i.e., towards the target tissue), the orientationidentifier (e.g., “PT”) is also oriented properly as shown in FIG. 11B.In other words, when the drug delivery device is placed correctly on thetargeted tissue site with the API layer side against the targetedtissue, the orientation identifier (e.g., the “PT”) can be legible andin the correct orientation for the surgeon to distinguish theorientation identifier.

Besides also having an orientation identifier, the portion of thenon-API layer that extends beyond the API layer can also be used tosuture the drug delivery device to the targeted tissue in the patient.FIG. 12 provides another example of the non-API layer with a rim 104extending beyond the API-layer. For example, after locating theorientation identifier of the drug delivery device and orienting thedrug delivery device properly, resorbable sutures such as 3-0 Vicrylwith SH needle attached or equivalent can be attached to the portion ofthe non-API layer (i.e., the rim) that extends beyond the API layer. Inaddition, one can also use Lapra-Ty® and absorbable suture clips. Assuch, once the suture is in place, clips can be placed to fix themwithout needing to tie knots, thereby possibly reducing time to placethe patch on the targeted tissue. In some embodiments, the sutures canbe placed at approximately evenly spaced locations around the rim. Forexample, four sutures can be placed at four approximately evenly spacedlocations around the rim representing the four cardinal directions.FIGS. 13A and 13B illustrate images showing location for attaching foursutures (FIG. 13A) and a sample of the sutured drug delivery deviceready to be implanted (FIG. 13B). This technique can allow surgeons toimplant more quickly by avoiding the added work of suturing through thepatch in the body. In some embodiments, another suture (e.g., adifferent color suture such as Prolene or equivalent) can be placed nearone of the cardinally placed sutures as another orientation identifier.For example, a different color suture can be placed clockwise near acardinally placed suture as another orientation identifier as shown inFIGS. 14A-B. This orientation identifying suture may not be used forfixation to the target tissue. Prior to attaching the sutures, if theimplant feels cool or stiff, it can be warmed by the hands or submergedin warm saline prior to attaching the sutures.

In some embodiments, drug delivery device can include anatomicalmarker(s). In some embodiments, an API layer and/or a non-API layer caninclude an anatomical marker(s). In some embodiments, the anatomicalmarker can be adhered or connected to the drug delivery device. In someembodiments, the anatomical marker(s) can be adhered or connected to anAPI layer and/or a non-API layer. The anatomical marker can be used by aphysician to identify the drug delivery device in the patient using awide variety of imaging techniques. The physician can then monitor theprogress and/or location of the drug delivery device with respect to thetumor. In some embodiments, the anatomical marker can be a radiopaquemarker, x-ray markers, lead markers, or similar marker(s).

Implantation

Next, the suture prepared drug delivery device can be folded and/orrolled into a tubular (e.g., cigar) shape just under the diameter (3 mmto 12 mm (e.g., 3, 5, 8, 10, 12 mm)) trocar (with sutures and intactneedle already tied on). In some embodiments, the drug delivery devicescan be folded and/or rolled just under 3 mm to 12 mm (e.g., 3, 5, 8, 10,12 mm trocar) depending on the trocar being utilized. For example, if a10 mm trocar is used during surgery, the suture prepared drug deliverydevice can be rolled into a tubular shape just under 10 mm in diameter.In some embodiments, the drug side can be on the inside or the outsideof the tubular roll. FIGS. 15A-D illustrates a rolled drug deliverydevice. Prior to rolling, if the implant feels cool or stiff, it can bewarmed by the hands or submerged in warm saline prior to rolling.

After being rolled, the drug delivery device can be inserted through theintended trocar port. The drug delivery device will typically unfurl andbecome flat once through the trocar. However, the drug delivery devicecan also be flattened out using typical surgical tools such aslaparoscopic bowel graspers. Once flattened, the drug delivery devicecan be guided onto the targeted tissue. Once on the target area, acamera can be utilized to make sure that the drug delivery device isproperly oriented. In other words, a surgical camera can be utilized tomake sure that the API layer is facing towards the targeted tissue. Asurgeon can look for an orientation identifier on the drug deliverydevice to determine proper orientation. For example, when the drugdelivery device is placed correctly on the targeted tissue with the APIlayer against the targeted tissue, the “PT” can be legible and in thecorrect orientation for the surgeon to distinguish the orientationidentifier. As such, the orientation identifier can be visible duringopen, laparoscopic, endoscopic, or robotic surgery. In some embodiments,the surgeon can use the camera to view the suture orientation identifieron the drug delivery product to confirm that the non-API layer is facingaway from the targeted tissue. For example, returning to FIG. 14A, ifthe surgeon sees that the suture orientation identifier is oriented asif in a mirror image, counterclockwise, the surgeon can flip the drugdelivery device over such that the suture orientation identifier isclockwise from the fixation suture prior to suturing in place. FIGS.16A-16B illustrate this point. Failure to confirm proper orientationcould result in release of the API to non-target sites.

Once the correct placement and orientation of the drug delivery deviceis confirmed, the drug delivery device can be sutured in place. Forexample, the drug delivery device can be sutured in place one at a timewith the previously attached sutures to the area around the targetedtissue and/or the targeted tissue itself. FIG. 17 illustrates an exampleof a drug delivery device sutured in place by sutures 106.

Drug Delivery Device Properties

In some embodiments, the drug delivery devices disclose herein can betransparent, medium to light brown with a clear rim indicating twosides. The drug delivery devices may have no visible foreign particulatematter on the surface or cracks. In addition, the orientation indicatorcan be clearly marked on the clear rim to allow the surgeon todistinguish the non-API side from the API side.

In some embodiments, the drug delivery device can be circular in natureif it was formed from a circular mold such as an evaporation dish or apetri dish. In some embodiments, the diameter of the drug deliverydevice can be at least about 1 cm, at least about 3 cm, at least about 5cm, or at least about 6 cm. In some embodiments, the diameter of thedrug delivery device can be at most about 10 cm, at most about 8 cm, atmost about 7 cm, or at most about 6 cm. In some embodiments, thediameter of the drug delivery device can be about 3-9 cm, about 4-8 cm,about 5-7 cm, about 5.5-6.5 cm, or about 6.1-6.3 cm.

In some embodiments, an outer perimeter of an API layer can be insetrelative to an outer perimeter of a non-API layer such that a portion(i.e., the rim) of a non-API layer extends beyond the API layer by anaverage of about 0.1-10 mm, about 0.5-8 mm, or about 1-5 mm around theperimeter of the API layer. This can be measured by a micrometer,average of n=5 measurements at 5 randomly selected points around thenon-API layer's rim of the drug delivery device.

The thicknesses of films were measured by the following protocol: (1)the API (first layer) layer was facing down; (2) the devices wereoriented so that three lines at 25%, 50%, and 75% down the device couldbe determined consistently; (3) the micrometer was calibrated to zerowhen fully closed (not forcefully tightened); (4) using the micrometer,the devices were measured at 5 different points along each line; (5)step 4 was repeated 3 times so that a total of 15 measurements wereavailable for each line. Four films containing a first layer of 0.8-1 gof PLGA 50:50, and 40-100 mg acetone and a second layer on a side of thefirst layer made up of 0.8-1 g PLGA 75:25 and 40-100 mg acetone) weretested. FIG. 18A illustrates the thickness measured at 3 differentpoints on the first device before refrigeration, FIG. 18B illustratesthe thickness measured at 3 different points on second device beforerefrigeration, FIG. 18C illustrates the thickness measured at 3different points on the third device after 4 weeks of refrigeration, andFIG. 18D illustrates the thickness measured at 3 different points on thefourth device after 11 weeks of refrigeration. The refrigerationtemperature was about 2-8° C. FIG. 19 illustrates the average thicknessfor the four example devices measured in accordance with someembodiments disclosed herein.

In some embodiments, the average thickness of the drug delivery devicecan be at least 10 microns, at least 25 microns, at least 50 microns, atleast 100 microns, at least 200 microns, at least 300 microns, at least400 microns, at least 500 microns, at least 550 microns, at least 600microns, at least 750 microns, at least 1000 microns, at least 1500microns, at least 2000 microns, at least 2500 microns, at least 3000microns, at least 3500 microns, at least 4000 microns, at least 4500microns, or at least 5000 microns. In some embodiments, the drugdelivery device can be at most 5000 microns, at most 4500 microns, atmost 4000 microns, at most 3500 microns, at most 3000 microns, at most2500 microns, at most 2000 microns, at most 1500 microns, at most 1000microns, at most 900 microns, at most 750 microns, at most 600 microns,at most 500 microns, at most 300 microns, at most 200 microns, or atmost 100 microns. In some embodiments, the average thickness of the drugdelivery device can be about 100-1500 microns, about 200-900 microns,about 300-900 microns, about 400-800 microns, about 430-730 microns,about 500-600 microns, or about 580 microns.

In some embodiments, the average thickness of an API and/or non-APIlayer can be at least 1 micron, at least 10 microns, at least 25microns, at least 50 microns, at least 100 microns, at least 250microns, at least 300 microns, at least 400 microns, at least 500microns, at least 750 microns, at least 1000 microns, at least 1500microns, at least 2000 microns, at least 2500 microns, at least 3000microns, at least 3500 microns, at least 4000 microns, or at least 4500microns. In some embodiments, the average thickness of an API and/ornon-API layer can be at most 5000 microns, at most 4500 microns, at most4000 microns, at most 3500 microns, at most 3000 microns, at most 2500microns, at most 2000 microns, at most 1500 microns, at most 1000microns, at most 750 microns, at most 600 microns, at most 500 microns,at most 400 microns, at most 350 microns, at most 300 microns, at most250 microns, at most 200 microns, at most 150 microns, at most 100microns, at most 50 microns, at most 25 microns, or at most 10 microns.In some embodiments, the average thickness of an API and/or non-APIlayer can be about 50-500 microns, about 100-450 microns, about 150-450microns, about 200-400 microns, about 215-365 microns, about 250-300microns, or about 290 microns. In some embodiments, the thickness of thedrug delivery device can be selected based on the desireddegradation/API release kinetics. The average thickness can be measuredby a micrometer, average of n=5 measurements at 5 randomly selectedpoints on the drug delivery device.

The diameter of the drug delivery device can be measured by thefollowing protocol: (1) the outer diameter (i.e., diameter of thenon-API layer) can be measured by placing the ruler along the diameter,which included the external rim of the non-API layer, and reading theruler carefully; (2) step 1 was repeated 15 times, moving the deviceeach time, so as to have a total of 15 readings; (3) the inner diameter(i.e., diameter of the API layer) was measured similarly, except thatthe external rim was not included in the measurement. FIGS. 20A-20Billustrates the diameters and average diameters for the four exampledevices measured in accordance with some embodiments disclosed herein.Accordingly, the average thickness and diameters of the drug deliverydevices do not change significantly under the intended storage condition(e.g., about 2-8° C.) over a period of time.

The diameters and thicknesses of 3 films containing a first layer of0.8-1 g of PLGA 50:50 and 40-100 mg acetone and a second layer on a sideof the first layer made up of 0.8-1 g PLGA 75:25 and 40-100 mg acetone)were tested to compare their dry vs. wet measurements. The films weremeasured at Day 0 (before being placed in buffer solution) and thenmeasured again after being placed in 60 mL of Sorenson's buffer after 1day, 7 days, and 14 days. FIG. 21A illustrates the average thickness forthe films measured dry vs. wet and FIG. 21B illustrates the averagediameters for the films measured dry vs. wet.

In order to determine if the API is contained only in the API layer aswell as evenly distributed in the API layer, a drug delivery devicecontaining a first layer of 0.8-1 g of PLGA 50:50, 100 mg paclitaxel,300 micrograms fluorescently labeled paclitaxel, and 40-100 mg acetoneand a second layer on a side of the first layer made up of 0.8-1 g PLGA75:25 and 40-100 mg acetone was viewed under a confocal microscope asshown in FIG. 22 . As seen in FIG. 22 , it appears that the API andnon-API layers are very distinct indicating that the paclitaxel can becontained only within the API layer and even distributed within the APIlayer. As such, the API layers of the drug delivery devices disclosedherein can have the API uniformly and homogeneously distributedthroughout the layer.

A set of 30 films containing a first layer of 0.8-1 g of PLGA 50:50 (andacetone) and a second layer on a side of the first layer made up of0.8-1 g PLGA 75:25 (and acetone) were degraded in vitro in aqueous mediato determine the rate of degradation of the polymer and water absorbedby the polymer. The films were placed in 15 mL of Sorenson's buffer(0.2M, pH 7.4) and incubated at 37° C. on a shaker set to 50 rpm.Samples were removed, dried, and weighed at time points between 1 dayand 10 weeks to establish mass loss at a variety of time points. Resultsof testing in these conditions demonstrated that the devices degradeslowly over the first week. At that point the rate of mass lossincreases, and the devices lose mass in a linear fashion. As such, thelayers of the drug delivery device (and the drug delivery device itself)can degrade substantially linearly or linearly. Only 10% of the initialpolymer mass remains at 10 weeks. Images taken of the discs at differenttime points also show that the PLGA 50:50 degrades more quickly than thePLGA 75:25, and appears to be fully degraded by the 6 week time pointindicating that the API would be fully released by 6 weeks. All testsamples were weighed and imaged prior to testing. Then each was placedin 15 mL of Sorenson's buffer (pH 7.4). Sample containers were sealedwith parafilm and placed on an incubating shaker set to 37° C. and 50rpm. Sample pH was tested and titrated with 1.0 N NaOH back to theacceptable pH range (7.4+/−0.3) each week. Samples were removed atpredetermined time points (1 day, 3 days, 5 days, 1 week, 2 weeks, 3weeks, 4 weeks, 6 weeks, 8 weeks, and 10 weeks). Removed samples wereimaged, weighed, and then placed in a petri dish covered with a kimwipe. The petri dish was then placed in a desiccator under vacuum for upto one week to dry. Dry samples were imaged a third time, and weighed.This allowed determination of polymer mass loss and water absorbedduring testing. For the 8 and 10 week time points, the sample solutionwas also filtered through grade 1 filter paper to collect visibleparticulates in the solution. The filters were preweighed and placed ina petri dish with the intact portion of the sample to dry. The weight ofthe particulate matter was included in the remaining weight of thesample. Images of the degradation samples before degradation, afterremoval from solution, and after drying can be found in FIGS. 23A-J.Over the first week (FIGS. 23A-D), samples hydrated, but did not appearto change substantially in comparison with their initial appearance oncethey were dried. At two weeks (FIG. 23E), there were some changes in theappearance of the films, and at 3 weeks (FIG. 23F) it was clear that thePLGA was degrading enough that it could be seen. The PLGA 50:50 layer istypically light to medium brown in color and the PLGA 75:25 is typicallyclear or white. In FIG. 23F, it appears that the PLGA 50:50 layer issignificantly degraded at the 3 week time point, and by 4 weeks (FIG.23G), most of the PLGA 50:50 is gone, and in one sample, the PLGA 75:25also started to degrade through. At 6 weeks (FIG. 23H), the remainingsample was very thin and brittle, which caused some samples to breakwhen dried. At 8 and 10 weeks (FIGS. 23I-J) little intact sampleremained, and particulate matter was collected from the solution byfiltration (not pictured). FIG. 24 illustrates a graph of percent massremaining over time (dry mass/initial mass*100). After a slow loss toabout 90% mass remaining over the first two weeks, the samples degradedmore rapidly over the following 8 weeks to approximately 10% massremaining. FIG. 25 shows the percent of water absorbed by the disc overtime ((wet mass−dry mass)/dry mass*100). Water appears to be absorbedslowly over the first two weeks, then increases rapidly as the polymerdegrades. Thus, it appears that the film degrades slowly over the firsttwo weeks, then degrades linearly after two weeks down to only 10%remaining at 10 weeks. The PLGA 50:50 appears to degrade first, and isalmost fully degraded at 4 weeks, and fully degraded at 6 weeks. ThePLGA 75:25 degrades to approximately 10% of the original mass of thedevice by 10 weeks.

In some embodiments, the drug delivery device can be configured torelease the API according to a defined release kinetic profile. In someembodiments, the release of the API can be delayed (or only asub-therapeutically effective amount of the API can be released duringthe delay period) after the device is implanted at the target tissuesite such that the patient's body can recover from the implantationsurgery prior to releasing the drug. The delay can allow for somehealing at the implantation site before the release of the API, therebypotentially reducing risks associated with swelling, perforation,bleeding, infection, and other potential issues. In some embodiments,the API delay release period can be at least 1 day, at least 3 days, atleast 7 days, at least 9 days, at least 10 days, at least 12 days, atleast 14 days, at least 16 days, at least 18 days, or at least 21 days.In some embodiments, the API delay release period can be at most 28days, at most 25 days, at most 21 days, at most 18 days, at most 15days, at most 14 days, at most 12 days, at most 10 days, at most 8 days,at most 7 days, at most 5 days, or at most 3 days. In some embodiments,the API delay release period can be 1-28 days, 1-21 days, 1-14 days, or7-14 days. After the delay period, the API can have a substantiallylinear or linear release rate.

Accordingly, an API layer with PLGA 50:50 can begin to release the APIat the target tissue at approximately 1 week after implantation and theAPI can be fully released by 4 weeks after implantation. This can alignwell with the degradation data—it takes time for the polymer to hydrate,but at 4 weeks most of the PLGA 50:50 is gone, so most of the API willhave been released. In addition, a non-API layer made with PLGA 75:25can serve as a mechanism that forces the API to be released only fromone face of the device. The PLGA 75:25 layer was thinned by 4-6 weeks,but only one sample formed a small hole before the PLGA 50:50 layer wascompleted degraded. This can prevent the API from leaking away from thetargeted tissue site as well as anchor the device to the target site.

The degradation of biodegradable polymer in an API layer can control therelease the API from the API layer during use. As such, degradation ofan API layer in the drug delivery device can be tuned based on thebiodegradable polymer in the API layer as well as the thickness of theAPI layer as the thicker the API layer the longer it will take todegrade. In some embodiments, the API layer can be configured tocompletely degrade within a period of at least 3 days, at least 5 days,at least 1 week, at least 2 weeks, at least 3 weeks, at least 3.5 weeks,at least 4 weeks, at least 30 days, at least 4.5 weeks, at least 5weeks, at least 6 weeks, at least 2 months, at least 3 months, at least4 months, at least 6 months, at least 8 months, or at least 10 months,after implantation. In some embodiments, the API layer can be configuredto completely degrade within a period of at most 2 years, at most 1year, at most 10 months, at most 8 months, at most 6 months, at most 4months, at most 3 months, at most 2 months, at most 6 weeks, at most 5weeks, at most 4.5 weeks, at most 30 days, at most 4 weeks, at most 3.5weeks, at most 3 weeks, at most 2 weeks, or at most 1 week, afterimplantation. In some embodiments, the API layer can be configured tocompletely degrade within a period of about 3 days to 10 months, 1 weekto 6 months, 1-6 weeks, about 2-6 weeks, about 3-5 weeks, about 3.5-4.5weeks, or about 4 weeks (about 30 days), after implantation. “Completelydegrade” or “fully degrade” used herein refers to a layer or devicedegrading to less than 10% of original mass within the time period. Insome embodiments, the API can be released from an API layer at a rate ofabout at least 1 mg API/day. In some embodiments, the API can bereleased from the API layer at a rate of about 1-10 mg/day, about 1-5mg/day, about 2-5 mg/day, or about 3-4 mg/day, after implantation. Insome embodiments, the API can be released from the API layer at a rateof about 7-70 mg/week, about 7-35 mg/week, about 14-35 mg/week, or about21-28 mg/week, after implantation. In some embodiments, the degradationprofile of the API layer (and the API release profile) afterimplantation can include a delay period from about 1 day to 2 weeks.After the delay period, the degradation of the API layer (and the APIrelease) can be substantially linear or linear.

Drug release (i.e., API release) was tested in vitro in a paddle overdisc (USP 5) apparatus (SOTAX). This setup is typically designed fortransdermal patches, however because this setup is designed to measureunidirectional release from a patch, it was the most appropriate setup.Specifically, drug delivery devices containing a first layer of 0.8-1 gof PLGA 50:50, 100 mg paclitaxel, and 40-100 mg acetone and a secondlayer on a side of the first layer made up of 0.8-1 g PLGA 75:25 and40-100 mg acetone) were placed in the SOTAX vessels with PLGA 50:50 sideup in 900 mL of 1.75M sodium salicylate in 1×PBS. The water bath was setto 37° C. and the paddles were set to a stir rate of 100 rpm. No discholder was placed in the vessel containing 104.67 mg paclitaxel as thecontrol. The paclitaxel for the positive control (+CTRL) was weighed ina glass scintillation vial and added to the vessel dry. 2 mL sampleswere taken at the following time points: 4 days, 1 week, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, and 10weeks. 2 mL of 1.75 sodium salicylate in 1×PBS was added after eachsampling. Samples were analyzed by HPLC using a diode array detector at229 nm. Expected concentrations of drug in each disc portion were basedon an assumption of 100 mg of drug in each device. A calibration curverelating area under the curve of the paclitaxel peak (or peaks inresponse to temperature degradation) to the concentration as made priorto sample testing. A linear formula to calculate concentration forsamples with concentrations within the range of the curve was made fromthe data. AUC of paclitaxel samples were then measured and concentrationwas calculated from the formula. If sample concentration fell above therange of the curve, samples were diluted to fall within the curve toensure accuracy. The weights of the three drug delivery devices (i.e.,discs without sterilization or oven drying) as well as the positivecontrol are shown in FIG. 32A. FIG. 32B illustrates the average releaseof the drug from the three drug delivery devices as well as the drugcontent of the positive control over time. Additional samples were alsotested that had been oven dried (three samples) and sterilized (2samples) except this time 3 mL samples were taken instead of 2 mLsamples. The samples oven dried were placed in the oven at 38° C. for 3days and the sterilized samples were sterilized by e-beam radiation. Theresults of the oven dried and sterilized drug delivery devices drugrelease compared to the positive control are shown in FIG. 33 and FIG.34 illustrates the drug release of an individual drug delivery devicewith oven drying and no sterilization. Results showed a 1-2 week delayof release of API, followed by steady linear release for 9 weeks.

In addition, degradation of a non-API layer in the drug delivery devicecan be tuned based on the biodegradable polymer in the non-API layer aswell as the thickness of the non-API layer. In some embodiments, thenon-API layer can be configured to degrade at a slower rate than an APIlayer such that the API is released toward the targeted tissue. In someembodiments, the non-API layer can be configured to degrade at the samerate as an API layer. In some embodiments, the non-API layer can beconfigured to degrade at a faster rate as an API layer. For example, insome embodiments, there may be a non-API layer on a side of the APIlayer that is tumor facing (and another non-API layer (i.e., a backinglayer) on the other side of the API layer opposite the first non-APIlayer). This first non-API layer can degrade faster than the API layersuch that there may be a delayed period for API release due to thedegradation of the non-API layer (i.e., non-backing layer) first.

In some embodiments, the non-API layer can be configured to completelydegrade within a period of at least 5 days, at least 1 week, at least 2weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6weeks, at least 8 weeks, at least 10 weeks, at least 11 weeks, at least12 weeks, at least 4 months, at least 5 months, at least 6 months, atleast 8 months, at least 10 months, or at least 1 year, afterimplantation. In some embodiments, the non-API layer can be configuredto completely degrade within a period of at most 3 years, at most 2years, at most 1 year, at most 10 months, at most 8 months, at most 6months, at most 4 months, at most 3 months, at most 12 weeks, at most 11weeks, at most 10 weeks, at most 8 weeks, at most 6 weeks, at most 5weeks, at most 4 weeks, at most 3 weeks, or at most 2 weeks, afterimplantation. In some embodiments, the non-API layer can be configuredto completely degrade within a period of about 1 week to 2 years, 1 weekto 1 year, 1 week to 6 months, about 4-14 weeks, about 6-12 weeks, about8-12 weeks, about 9-11 weeks, or about 10 weeks, after implantation.

As explained above, in order for the device to be implanted via open,laparoscopically, robotically, endoscopically, the drug delivery devicecan be flexible enough and/or small enough to be able to pass through atrocar or other working channel of an endoscope (e.g., roboticendoscope). A study was conducted to determine whether the surfaces ofthe device or the API content of the device is altered by passagethrough a trocar. Specifically, drug delivery devices containing a firstlayer of 0.8-1 g of PLGA 50:50, 90-105 mg paclitaxel, and 40-100 mgacetone and a second layer on a side of the first layer made up of 0.8-1g PLGA 75:25 and 40-100 mg acetone) were passed through a 10 mm trocar10 times. The samples were observed before and after, their thicknesseswere measured before and after, and sample drug content was measured andcompared with drug content of samples that have never been passedthrough a trocar. Some surface scratching was observed under microscope,but no differences in drug content were found. During handling, the drugdelivery devices passed through the trocar easily. No differences wereobserved between the group of devices that was measured, weighed, andimaged, and the group of devices that was measured, weighed, imaged, andhandled through the trocar. There were no visible changes, such asscratching of the surface, visible in the majority of the images. Theclearest damage in any device appeared to have been caused to a controldrug delivery device during micrometer measurements. There was no changeto the dimensions or weight of the drug delivery devices. Finally, therewas no difference in drug content between groups, which would haveindicated drug content coming off in the trocar as measured bydissolving the device in acetonitrile and diluted 1000× for HPLCanalysis in an Agilent HPLC.

Cancer Treatment

In some embodiments, the targeted tissue may be tissue associated withvarious organs throughout the body including, but not limited to,pancreas, biliary system, gallbladder, esophageal system, liver,stomach, peritoneum, small bowel, lung, colon, or metastasis from aprimary tumor. For example, the targeted tissue may be canceroustissue/cells (e.g., a tumor or tumors) on the pancreas, biliary system,gallbladder, esophageal system, liver, stomach, peritoneum, small bowel,lung, colon, or metastasis from a primary tumor. As such, the drugdelivery devices disclosed herein can be used for treating many diseasesincluding tumors of various organs throughout the body including thepancreas, biliary system, gallbladder, esophageal system, liver,stomach, peritoneum, small bowel, lung, colon, or metastasis from aprimary tumor. Specifically, the various cancers that the drug deliverydevice can help treat include, but are not limited to, pancreatic ductaladenocarcinoma (PDAC), cholangiocarcinoma, gallbladder cancer, lymphoma,non-small cell lung cancer, or metastatic tumors. In some embodiments,the drug delivery devices can be used to treat resectable cancers and/ornon-resectable cancers. In some embodiments, the drug delivery devicesherein can be used to treat non-immediately resectable to non-metastaticcancers. In some embodiments, the drug delivery devices can be used totreat patients after cancers are resected to prevent recurrences. Forexample, the drug delivery devices can be used for treatment of patientswith borderline resectable or locally advanced pancreatic adenocarcinomaor lung cancers (e.g., non-small cell lung cancer). In some embodiments,the cancer treated by the drug delivery device can be a tumor in thetissue of primary origin or metastatic spread to the tissue. In someembodiments, the drug delivery devices can be used for treatment ofpatients with non-immediately resectable cancer, non-metastatic cancer,borderline resectable cancer, resectable cancer, locally advancedcancer, metastatic cancer, and/or metastasis from a primary tumor.

In some embodiments, the drug delivery devices disclosed herein can beplaced onto a peritumoral area of interest (API layer facing and incontact with peritumoral area of interest) and can biodegrade within thebody of the patient in about 1 week to 2 years, about 1-52 weeks, about1-26 weeks, about 1-24 weeks, about 1-20 weeks, about 1-15 weeks, about4-12 weeks, about 6-12 weeks, about 8-12 weeks, about 9-11 weeks, orabout 10 weeks of implantation. In some embodiments, the tumor may be onthe inside of the organ (i.e., not on the surface) and the drug deliverydevice is placed on the peritumoral surface of the organ. As explainedabove, the drug delivery device can be placed directly onto aperitumoral area of interest (e.g., around a pancreatic tumor) usingminimally invasive standard surgical techniques during routinelyperformed staging evaluations. In some embodiments, multiple drugdelivery devices can be placed directly onto a peritumoral area ofinterest. In some embodiments, the drug delivery device can be rolledinto a tube shape, inserted through surgical procedure, placed on theperitumoral area of interest, and sutured into place. In someembodiments, the size of the drug delivery device (e.g., diameter orsurface area) can allow the surgeon to cover the targeted tissue site(e.g., the pancreatic head and neck and for the edges to drape over theregion near the superior mesenteric artery and superior mesentericvein).

In some embodiments, the degradation of the API layer can control therelease of the API for a period of at least 3 days, at least 5 days, atleast 1 week, at least 2 weeks, at least 3 weeks, at least 3.5 weeks, atleast 4 weeks, at least 30 days, at least 4.5 weeks, at least 5 weeks,at least 6 weeks, at least 2 months, at least 3 months, at least 4months, at least 6 months, at least 8 months, or at least 10 months,after implantation. In some embodiments, the degradation of the APIlayer can control the release of the API for a period of at most 2years, at most 1 year, at most 10 months, at most 8 months, at most 6months, at most 4 months, at most 3 months, at most 2 months, at most 6weeks, at most 5 weeks, at most 4.5 weeks, at most 30 days, at most 4weeks, at most 3.5 weeks, at most 3 weeks, at most 2 weeks, or at most 1week, after implantation. In some embodiments, the degradation of theAPI layer can control the release of the API for a period of about 3days to 10 months, 1 week to 6 months, 1-6 weeks, about 2-6 weeks, about3-5 weeks, about 3.5-4.5 weeks, or about 4 weeks (about 30 days), afterimplantation. In some embodiments, the biodegradable polymer in the APIlayer can provide controlled and sustained release of the API over thisperiod during which the cancer-facing side of the device is absorbedinto the body. In some embodiments, the non-cancer-facing side (non-APIlayer) of the device, can help ensure that the drug delivery devicemaintains contact with the targeted tissue (e.g., tumor) during drugrelease and can help prevent release drug delivery device from the areaof interest. This non-API layer can then completely degrade after theAPI layer has completely degraded and released the entirety of the API.FIG. 26 illustrates an exemplary flowchart of how drug delivery devicesdisclosed herein can attack live tumor cells in some embodiments. Insome embodiments, a non-API layer can completely degrade at the sametime or faster than the API layer.

Large animal (i.e., pigs) and human cadaver studies show that the drugdelivery devices disclosed herein can be successfully deployed to theperitumoral pancreatic surface of the pancreas by a standardlaparoscopic procedure. Specifically, two 30-day studies in porcinemodels were conducted to assess safety, toxicity, and biodistribution.Parameters included body weights, hematology, urinalyses, drug levels inthe blood and at the implantation site, and histomorphologic evaluationof major organs. In both studies, the drug delivery device was designedto locally deliver paclitaxel over a 30 day period. In the first study,the drug delivery device was laparoscopically implanted onto theperitoneal surface to test feasibility and issue tolerance ofpaclitaxel. In the second study, the drug delivery device was placeddirectly onto the ventral surface of the healthy porcine pancreas in anopen operation. This is shown in FIGS. 27A-27B. Blood samples forpaclitaxel analysis were collected on Day 0 (prior to and postimplantation), twice weekly thereafter, and on Day 31 (prior tonecropsy), processed for plasma, stored frozen, and sent for paclitaxellevel analysis. The animals were euthanized on Day 31, and a limitednecropsy was performed. All frozen plasma and designated tissue sampleswere processed and analyzed for paclitaxel content by LC-MS accordingthe appropriate laboratory methods and standard operating procedures atthe test site. A protein precipitation extraction method was used forplasma and tissue samples, with homogenization of the tissue samples.For device testing, all samples were soaked 9:1 (v:w) of 0.5% formicacid in methanol and sonicated in an ice bath for 30 minutes. Thesolution was transferred into a new container on ice. The process wasrepeated two additional times. A final 9:1 v:w (rinse) was added andtransferred to the final vial. Implant and tissue samples wereparaffin-processed and stained with H&E for histomorphologic assessment.Light microscopy was used for characterization of the host responseusing standard nomenclature of pathology including type of inflammation,fibrosis, collagen deposition/content, and vascularity/vascularintegration.

The animals appeared healthy for the full 30 days in both studies,without showing debilitating effects usually associated with IVadministration of chemotherapy (weight gain was expected in case ofhealthy pig not receiving chemo as shown in FIG. 28 while in case ofchemo IV weight was expected to go down). After 30 days of paclitaxelrelease in vivo, the non-API backing layer was still present at theimplant sites without signs of migration. The underlying tissue in theabdominal wall showed some visible redness, but histology showed minimalhemorrhage and necrosis as shown in FIG. 29 . The underlying tissue inthe pancreas showed some thin capsule and fibrosis but minimal effect onthe surrounding structure as shown in FIG. 30 . The drug was releasedand primarily accumulated beneath the drug delivery device atconcentration up to 40 microM (as shown in FIG. 31 ). Serum paclitaxellevels were measured below quantitation limits throughout the 30 days oftreatment, validating the ability of the drug delivery device to deliverthe drug only at its intended site. As such, there does not appear to beany diffusion outside of the area of interest.

To validate the feasibility of minimally invasive surgical insertion,the drug delivery device disclosed herein was laparoscopically placeddirectly on the pancreas of three human cadavers. The drug deliverydevice was consistently and effectively placed during a minimallyinvasive surgery without substantial increase in procedure time. Morespecifically, the time up to pancreas visualization during thelaparoscopic procedure took about 25 minutes and the amount of time forthe drug delivery device placement and suturing on the pancreas tookabout 10-25 minutes, about 10-20 minutes, or about 15-20 minutes. Assuch, placing the drug delivery device at the target site only slightlyincreased the procedure time. The drug delivery device conformed fullyto pancreatic tissue, allowing for close contact with the intendedtissue for drug delivery, and can cover the areas of the pancreas wherecritical involvements of tumors with vasculature are commonly found.

Lastly, the drug delivery devices disclosed herein have been used inthree patients for a Phase I Clinical Trial. The three patients weresuffering from locally advanced pancreatic ductal adenocarcinoma (PDAC)and were treated with a drug delivery device in the shape of a circularpatch containing a first layer of 1 g of PLGA 50:50, 90-105 mgpaclitaxel, and 40-100 mg acetone and a second (backing layer) on a sideof the first layer made up of 1 g PLGA 75:25 and 40-100 mg acetone.

Prior to implantation, the surgeons prepared each of the drug deliverydevices by placing sutures at four evenly spaced locations around theedge of the second layer, approximate the four cardinal directions forthe circular drug delivery device. The patch was placed via a trocardirectly onto the pancreatic surface overlying the tumor using standardlaparoscopic surgical equipment after a diagnostic laparoscopy confirmedthe subjects were negative for visual metastatic disease. The implantprocedure took between 18-32 minutes for all three patients treated todate. The device was oriented correctly on the pancreas and placedsuccessfully in all cases with paclitaxel layer facing the pancreas. Noadverse event or device malfunctions were reported during any of theprocedures. Ease of preparation was rated as very easy for allprocedures and placement was rated either very easy or not difficult.

Before implantation and at various time points after implantation,volumetric, transversal, and anterior/posterior measurements of thetumors were taken for each patient. Specifically, the transversal (T)measurement can be the length of the largest dimension of the tumor. Theanterior/posterior (AP) dimension or diameter can be the length of thetumor orthogonal to the drug delivery device. In some embodiments, theanterior/posterior dimension or diameter can be the length of the tumorin the direction of drug release/delivery. In some embodiments, theanterior/posterior dimension can be the largest dimension of the tumororthogonal to the drug delivery device. The transversal dimension can bemeasured manually by reader on the longest diameter tumor slice in CTsoftware. The anterior-posterior diameter can be measured manually byreader on longest diameter tumor slice orthogonal to the drug deliverydevice in CT software. The volume of the tumor can be measured by lesiondelineated on axial view by reader on each tumor slice calculated by 3Dsoftware.

In addition, the patients' blood can be tested for CA 19-9 using astandard lab test and for paclitaxel using a pharmacokinetic assay.Standard RECIST (Response Evaluation Criteria in Solid Tumors)measurements were used to determine clinical outcomes (e.g., partialresponse, remains unresectable, metastatic, primary stable/progress,stable disease, etc.).

All patients began modified FOLFIRINOX (oxaliplatin, Leucovorin,Fluorouracil, and Irinotecan) 21 days (±7 days) after deviceimplantation. The third patient had their dose increased after the firstcycle of treatment and the first patient also had radiotherapyapproximately 7 months post device implantation to treat their tumorafter systemic chemotherapy was completed.

This Phase I Clinical Trial preliminarily demonstrated (as study isstill ongoing) a local response in the initial cohort of patients, anexcellent safety profile (e.g., well tolerated in all patients with noSAEs, no peritonitis, pancreatitis, infection, or hematologic toxicityas well as no detectable level of paclitaxel systemically), and minimalincrease in operating room time for drug delivery device deployment(i.e., less than about 20 minutes).

The first patient had a locally advanced disease. The implantationprocedure time took 25 minutes for the first patient and the clinicaloutcome was partial response, remains unresectable. FIG. 35A illustratesa graph of the tumor's largest dimension in the first patient over 23weeks and FIG. 35B illustrates the data collected regarding tumor volumeand size over 23 weeks. As shown by FIG. 35B, the volume of the firstpatient's tumor reduced by 11% in two weeks after implantation beforesystemic chemotherapy started and reduced by over 70% in 23 weeks afterimplantation. In addition, the largest dimension of the tumor saw a 50%decrease in 23 weeks after implantation and the anterior/posteriordimension of the tumor reduced by 27% in that same time period. FIGS.36A-40B illustrate radiographical images of the tumor (as dashed line)of the first patient as well as 3D renderings of the tumor at baseline,2 weeks post-implant pre-chemo, 10 weeks post-implant pre cycle 5, 16weeks post-implant pre cycle 9, and 24 weeks post-implant pre cycle 12.The first patient's latest visit was at the 12 month mark and theclinical outcome was RECIST partial response, remains unresectable.

The second patient had a locally advanced disease. The implantationprocedure time took 18 minutes for the second patient and the clinicaloutcome was metastatic, primary stable/progressed. The second patientpresented with a large tumor and distant metastasis was identified atthe 3-month visit. It is possible that the subject already hadmetastatic disease at the time of presentation that had not beendiagnosed. Despite the distant disease progression, the second patientstill experienced a reduction in the anterior/posterior direction of thetumor and the tumor remained stable indicating that the subject receivedthe benefits of local treatment. FIG. 41A illustrates a graph of thetumor's largest dimension in the second patient. The “*” in the graphequates to failed systemic chemo treatment and that the patient showedmetastatic disease. FIG. 41B illustrates the data collected regardingtumor volume and size. As shown in FIG. 41B the length in theanterior/posterior direction of the tumor still decreased by 16%. FIGS.42A-45B illustrate radiographical images of the tumor (as dashed lines)of the second patient as well as 3D renderings of the tumor at baseline,2 weeks post-implant pre-chemo, 10 weeks post-implant pre cycle 5, and16 weeks post-implant pre cycle 9. The second patient's latest visit wasat the 6 month mark and the clinical outcome was RECIST metastatic,primary stable/progressed.

The third patient also had locally advanced disease. The implantationprocedure time took 32 minutes for the third patient and the clinicaloutcome was stable disease. FIG. 46A illustrates a graph of the tumor'slargest dimension in the third patient and FIG. 46B illustrates the datacollected regarding tumor volume and size. The “*” shown in FIG. 46A isto point out that the analysis for transversal dimension used week 2data due to baseline uncertainty. FIGS. 47A-51B illustrateradiographical images of the tumor (as dashed line) of the third patientas well as 3D renderings of the tumor at baseline, 2 weeks post-implantpre-chemo, 10 weeks post-implant pre cycle 5, 16 weeks post-implant precycle 9, and 24 weeks post-implant pre cycle 12. The second patient'slatest visit was at the 9 month mark and the clinical outcome was RECISTstable disease.

From the three patients in the clinical trial, the drug delivery devicewas easily integrated into laparoscopic procedures. The device wassuccessfully implanted using standard laparoscopic setup, there wasminor increase in procedure time, and there is opportunity to furtherreduce time with robotic procedure and/or optimization as shown in FIG.52 .

FIG. 53 illustrates the reduction in tumor size of the first patientfrom the clinical trial. As stated above, the first patient's tumorreduced from baseline greater than 70%. In addition, there was a higherresponse in antero-posterior direction (in the direction of drugrelease) measured in the axial plane with significant bulging effectreduction of the pancreatic lesion at pre-cycle 5 and confirmed on nextvisits.

FIG. 54 illustrates tumor volumetric change from baseline for the threepatients in the clinical trial. The drastic tumor volume reduction forthe first patient (˜70%) and the third patient (˜40%) was confirmed atthe latest scans. In addition, the second patient who failed systemictreatment and progressed to metastatic showed minimal local volumetricchange. As such, the drug devices disclosed herein can stabilize and/orreduce tumor size (e.g., volume, transverse dimension, oranterior/posterior dimension).

FIG. 55 illustrates tumor anterior/posterior reduction of the threepatients. This strong reduction response in anterior/posterior diameterhelps illustrate the drug delivery device's ability to unidirectionallyrelease the API onto the tumor. This can also be shown in FIG. 53 withthe implant shown as the dash-dot line, the tumor 2 weeks post-implantshown by the short dashed line, and the tumor 24 weeks post-implantshown in the long dashed line. As you can see by the arrow in FIG. 53 ,the tumor shrunk in the anterior/posterior direction (i.e., thedirection orthogonal to the drug delivery device).

FIGS. 56A-B illustrate the amount of CA 19-9 in the three patients'blood from the clinical trial over time. As shown in the figures, thefirst and third patients experienced a drop from baseline to day 21 of28-37%. The second patient had metastatic disease but did show a slightreduction from day 7 to day 14 of 21%. The “*” in FIG. 56A shows thatday 14 data for patient three was the same as day 7 for continuity.

Furthermore, no SAEs were reported in the 28-day safety window andbeyond in any patients. There was no evidence of pancreatitis,peritonitis, or infection. There was no detectable paclitaxel inperipheral blood sampling in any patients. In addition, there was nodelay in initiation of planned systemic therapy. As such, the drugdelivery devices disclosed herein can behave as predicted in preclinicalexperiments and encourage local disease control in advanced cohort.

The drug delivery devices disclosed herein can stabilize and/or reducethe size of a tumor after implantation on a tumor. Specifically, thedrug delivery devices disclosed herein can reduce the volume of a tumorby at least 10%, at least 20%, at least 30%, at least 40%, at least 50%,at least 60%, or at least 70% (with 100% reduction being the tumordisappearing) after implantation. The drug delivery devices disclosedherein can reduce the largest dimension of a tumor by at least 5%, atleast 10%, at least 25%, at least 40%, or at least 50% afterimplantation. The drug delivery devices disclosed herein can reduce theanterior/posterior dimension of the tumor (i.e., orthogonal dimensionfrom drug delivery device) by at least 10%, at least 15%, at least 20%,or at least 25% after implantation. In some embodiments, the change intumor volume, tumor largest dimension, and/or tumor anterior/posteriordimension can be within ±10% or ±5% after implantation of the drugdelivery device. In some embodiments, the reduction in size of thetumor, the reduction in tumor volume, the reduction in the largestdimension of the tumor, and/or the reduction of the anterior/posteriordiameter orthogonal to the drug delivery device can be after the drugdelivery device has completely dissolved in the patient, after the drugdelivery device has partially dissolved in the patient, and/or after aportion of the drug delivery device (e.g., the API layer) has completelydissolved in the patient.

In some embodiments, the drug delivery devices and methods disclosedherein can be used together with systemic chemotherapy, radiationtherapy, and/or surgery. In some embodiments, the drug delivery devicesand methods disclosed herein can improve tumor penetration of systemicchemotherapy in a patient. In some embodiments, systemic chemotherapycan be administered (or start being administered) after implantation(e.g., two weeks, 3 weeks, 4 weeks, etc. after implantation) of the drugdelivery device. In some embodiments, systemic chemotherapy can beadministered (or start being administered) at least 1 week, at least 2weeks, at least 3 weeks, at least 4 weeks, at least 3 months, at least 6months, or at least one year after implantation of the drug deliverydevice.

The drug delivery devices disclosed herein can change the route ofadministration to target just the area of interest, thereby increasingthe amount of drug reaching the tumor with the aim to enhancetherapeutic efficacy. As such, the drug delivery device can be appliedin patients with PDAC (among other cancers): (i) pre-operatively asneoadjuvant treatment to control progression and downsize locallyadvanced and borderline anatomy to improve resectability; (ii)post-resection to reduce the rate of local recurrence; or (iii) inmetastatic patient to control local progression and improve quality oflife.

Additional Definitions

Unless defined otherwise, all terms of art, notations and othertechnical and scientific terms or terminology used herein are intendedto have the same meaning as is commonly understood by one of ordinaryskill in the art to which the claimed subject matter pertains. In somecases, terms with commonly understood meanings are defined herein forclarity and/or for ready reference, and the inclusion of suchdefinitions herein should not necessarily be construed to represent asubstantial difference over what is generally understood in the art.

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”. In addition, reference to phrases “less than”, “greater than”,“at most”, “at least”, “less than or equal to”, “greater than or equalto”, or other similar phrases followed by a string of values orparameters is meant to apply the phrase to each value or parameter inthe string of values or parameters. For example, a statement that alayer has a thickness of at least about 5 cm, about 10 cm, or about 15cm is meant to mean that the layer has a thickness of at least about 5cm, at least about 10 cm, or at least about 15 cm.

As used herein, the singular forms “a,” “an,” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It is also to be understood that the term “and/or” as usedherein refers to and encompasses any and all possible combinations ofone or more of the associated listed items. It is further to beunderstood that the terms “includes, “including,” “comprises,” and/or“comprising,” when used herein, specify the presence of stated features,integers, steps, operations, elements, components, and/or units but donot preclude the presence or addition of one or more other features,integers, steps, operations, elements, components, units, and/or groupsthereof.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, one or more of the following: alleviating one ormore symptoms resulting from the disease, diminishing the extent of thedisease, stabilizing the disease (e.g., preventing or delaying theworsening of the disease), preventing or delaying the spread (e.g.,metastasis) of the disease, preventing or delaying the recurrence of thedisease, delay or slowing the progression of the disease, amelioratingthe disease state, providing a remission (partial or total) of thedisease, decreasing the dose of one or more other medications requiredto treat the disease, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival. Alsoencompassed by “treatment” is a reduction of a pathological consequenceof a cancer. The methods of the invention contemplate any one or more ofthese aspects of treatment.

This application discloses several numerical ranges in the text andfigures. The numerical ranges disclosed inherently support any range orvalue within the disclosed numerical ranges, including the endpoints,even though a precise range limitation is not stated verbatim in thespecification because this disclosure can be practiced throughout thedisclosed numerical ranges.

The above description is presented to enable a person skilled in the artto make and use the disclosure, and is provided in the context of aparticular application and its requirements. Various modifications tothe preferred embodiments will be readily apparent to those skilled inthe art, and the generic principles defined herein may be applied toother embodiments and applications without departing from the spirit andscope of the disclosure. Thus, this disclosure is not intended to belimited to the embodiments shown, but is to be accorded the widest scopeconsistent with the principles and features disclosed herein.

1. A drug delivery device comprising: a first layer comprising an activepharmaceutical ingredient (API) and at least 50 wt. % of a firstbiodegradable polymer; and a second layer on a side of the first layer,the second layer comprising at least 70 wt. % of a second biodegradablepolymer, wherein the second biodegradable polymer has a slowerdegradation rate than the first biodegradable polymer.
 2. The device ofclaim 1, wherein an outer perimeter of the first layer is inset relativeto an outer perimeter of the second layer such that a portion of thesecond layer extends beyond the first layer.
 3. The device of claim 2,wherein the portion of the second layer extends beyond the first layerby 1-5 mm.
 4. The device of claim 2, wherein the portion of the secondlayer that extends beyond the first layer comprises an orientationidentifier.
 5. The device of claim 1, wherein the first biodegradablepolymer is poly(lactic-co-glycolic acid) (PLGA) 50:50.
 6. The device ofclaim 5, wherein the second biodegradable polymer is PLGA 75:25.
 7. Thedevice of claim 1, wherein the first layer comprises 1-30 wt. % API. 8.The device of claim 1, wherein the first layer comprises a solvent. 9.The device of claim 8, wherein the first layer comprises 1-15 wt. %solvent.
 10. The device of claim 9, wherein the solvent is acetone. 11.The device of claim 1, wherein the second layer comprises a solvent. 12.The device of claim 11, wherein the second layer comprises 1-15 wt. %solvent.
 13. The device of claim 12, wherein the solvent is acetone. 14.The device of claim 1, wherein the API is paclitaxel.
 15. The device ofclaim 1, wherein the average thickness of the drug delivery device is10-5000 microns.
 16. The device of claim 1, wherein the drug deliverydevice is flexible such that it can be implanted in a patient usingstandard open and minimally invasive procedures.
 17. The device of claim1, wherein the drug delivery device is configured to be rolled to fitthrough a 3-12 mm trocar.
 18. A method of preparing a drug deliverydevice comprising: adding a first solution comprising a firstbiodegradable polymer, an active pharmaceutical ingredient (API), and asolvent to a mold; drying the first solution in the mold to form a firstlayer; adding a second solution comprising a second biodegradablepolymer and a solvent over the first layer in the mold, wherein thesecond biodegradable polymer degrades slower than the firstbiodegradable polymer; drying the second solution in the mold to form asecond layer on a side of the first layer; removing the multi-layereddrug delivery device from the mold.
 19. The method of claim 18, furthercomprising heating the multi-layered drug delivery device in an ovenafter removing from the mold.
 20. The method of claim 19, wherein themulti-layered drug delivery device is in the oven at 35-45° C. for 2-4days.
 21. The method of claim 18, further comprising marking the secondlayer of the multi-layered drug delivery device with an orientationidentifier.
 22. The method of claim 18, further comprising sealing themulti-layered drug delivery device in a pouch.
 23. (canceled) 24.(canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)
 28. (canceled)29. (canceled)
 30. (canceled)
 31. (canceled)
 32. (canceled) 33.(canceled)
 34. (canceled)
 35. (canceled)
 36. The method of claim 18,further comprising before adding and drying the second solution in themold to form the second layer, adding a third solution comprising athird biodegradable polymer, an active pharmaceutical ingredient (API),and a solvent over the first layer in the mold and drying the thirdsolution in the mold to form a third layer between the first and secondlayers.
 37. The method of claim 18, further comprising adding a fourthsolution comprising a fourth biodegradable polymer and solvent over thesecond layer in the mold and drying the fourth solution in the mold toform a fourth layer on a side of the second layer.
 38. A method oftreating tissue of a patient, comprising: implanting a drug deliverydevice onto a target tissue site of a patient, the device comprising: afirst layer comprising an active pharmaceutical ingredient (API) and atleast 50 wt. % of a first biodegradable polymer; and a second layer on aside of the first layer, the second layer comprising at least 70 wt. %of a second biodegradable polymer, wherein the second biodegradablepolymer has a slower degradation rate than the first biodegradablepolymer, wherein the drug delivery device is implanted such that thefirst layer is facing towards the target tissue site; releasing the APIfrom the first layer to the target tissue site, wherein the release ofthe API is controlled by in vivo degradation of the first biodegradablepolymer at the target tissue site.
 39. The method of claim 38, whereinimplanting the drug delivery device comprises suturing the drug deliverydevice to the target tissue site or an area around the target tissuesite.
 40. The method of claim 39, wherein the second layer is sutured tothe target tissue site or an area around the target tissue site.
 41. Themethod of claim 38, wherein the target tissue site is a peritumoral areaof the pancreas, biliary system, gallbladder, esophageal system, liver,stomach, peritoneum, small bowel, lung, colon, or metastasis from aprimary tumor.
 42. The method of claim 38, wherein the drug deliverydevice is implanted such that the first layer is in direct contact withthe target tissue site.
 43. The method of claim 38, wherein the firstlayer completely degrades within a period of 1 week to 10 months afterimplantation.
 44. The method of claim 38, wherein the second layercompletely degrades within a period of 2 weeks to 1 year afterimplantation.
 45. The method of claim 38, wherein the release rate ofthe API is 1-10 mg/day.
 46. The method of claim 38, wherein the drugdelivery device is implanted via open surgery, laparoscopically,robotically, percutaneously, or endoscopically.
 47. The method of claim46, wherein the drug delivery device is folded to fit through a trocarprior implantation.
 48. The method of claim 38, wherein the second layeris configured to prevent API leakage away from the target tissue site.49. The method of claim 38, wherein the drug delivery device is used asa neoadjuvant therapy.
 50. The method of claim 38, wherein the releaseof the API follows a delay period of about 1-14 days after implantation.51. The method of claim 50, wherein a sub-therapeutically effectiveamount of the API is released during the delay period.
 52. The method ofclaim 38, wherein releasing the API from the first layer to the targettissue site comprises releasing the API unidirectionally away from thesecond layer.